KR20190137788A - Stable Peptide Composition - Google Patents

Abstract

The present application generally relates to kits comprising stable peptide compositions and low levels of buffers and chelating agents, and methods of using the same.

Description

Stable Peptide Composition

Cross Reference to Related Application

This application claims priority to US Provisional Patent Application No. 62 / 530,565, filed July 10, 2017, and US Provisional Patent Application No. 62 / 461,467, filed February 21, 2017, Each of which is incorporated herein by reference in its entirety.

Explanation of Federally Supported R & D

The present invention was made with government support under R01EY024327 granted by the National Institutes of Health. The government has certain rights in the invention.

Reference to Sequence Listing

Substances in the appended sequence listings are incorporated herein by reference. The attached sequence listing text file named TEAR.003WO.TXT was created on February 14, 2018 and is 7.18 KB. The contents of the Sequence Listing are hereby incorporated by reference in their entirety.

Technical Field

The present application relates to the technical fields of chemistry, biochemistry and medicine. More specifically, many embodiments of the present application relate to stable, diluted peptide compositions and kits comprising such compositions. Specifically, many embodiments of the present application describe compositions comprising citrate, EDTA, and aqueous solutions of peptides, which are at room temperature (eg, 20 ° C. to 25 ° C.), with or without surfactants. Stable.

Description of the related technology

Polypeptides are increasingly recognized as potential therapeutics. As a result, there is increasing interest in using polypeptides in pharmaceutical research and development. However, it is well known that polypeptides are difficult to formulate with additives used, for example, to preserve or stabilize formulations that cause unwanted side effects.

summary

There is no need for a peptide composition that provides a therapeutic amount of peptide, is stable at room temperature, contains only trace amounts of stabilizers and / or preservatives, or contains no at all. To address this need and others, many embodiments of the present application provide stable polypeptide compositions. Advantageously, in some embodiments, the peptide (or combination of peptides) is stable in the composition of the present application to allow long term storage and / or delivery over an extended period of time. As such, these peptide compositions are stable at non-refrigerated temperatures without the need for reconstitution and are functional over a range of temperatures including temperatures in the range of 0-30 ° C. Indeed, certain embodiments of the present application find that diluted peptide compositions comprising low levels of EDTA in combination with low levels of citrate buffer remain effective after storage at room temperature, even such compositions are typically found in polypeptide compositions. It is based, in part, on the surprising and unexpected finding that it contains additives at substantially lower levels than those made.

Some embodiments include about 0.00001% -0.1%, 0.001% -0.1% (eg, 0.01% or 0.005% or 0.001%) of a polypeptide, or a pharmaceutically acceptable salt thereof; About 0.03% -3% (eg 0.2888%) buffer; Absent or about 0.0001% -0.01% (eg, 0%, or 0.001%) of disodium EDTA; A composition comprising, consisting of, or consisting essentially of, or from about 0.005% -0.5% (eg, 0%, or 0.05%) tiloxapol, and sodium chloride (eg, 0.5%). Providing a (eg liquid) composition; Wherein the pH of the composition is about 6.2 to about 6.8, and the osmolality of the composition is about 150-500 mOsm / kg or more (eg, 250 to 350) mOsm / kg. Liquid compositions include, but are not limited to, combinations, mixtures, solutions, gel compositions, and ointments.

In some embodiments, the buffer is citrate buffer. In some embodiments, the citrate buffer comprises about 0.001% -0.1% (eg 0.0098%) citric anhydride and about 0.02% -2% (eg 0.279%) sodium citrate dihydrate . In some embodiments, the pH of the composition is about 6.5.

In some embodiments, the osmolarity of the composition is about 280 to about 320 mOsm / kg. In some embodiments, the osmolarity of the composition is about 300 mOsm / kg. In some embodiments, the amount of NaCl is 0.4% to 0.6% (eg, about 0.5%).

In some embodiments, the composition further comprises parabens such as methylparaben (eg, 0.04% or less). In alternative embodiments, no parabens or other preservatives are included. In some embodiments, the composition further comprises sodium chlorite.

Some embodiments provide a kit comprising a plurality of sterile disposable containers, wherein each container comprises a vessel for holding the composition. In some embodiments, the container contains about 0.03 mL to about 1 mL (eg, 0.040 mL, 0.050 mL, 0.060 mL, 0.070 mL, 0.075 mL, 0.1 mL, 0.15 mL, 0.2 mL, 0.25 mL 0.3 mL, 0.35 mL) , 0.4 mL, 0.45 mL, 0.5 mL, 0.6 mL, 0.7 mL, 0.8 mL, 0.9 mL). In some embodiments, the container is for daily use, weekly use or longer term use. In one embodiment, a 1 mL-30 mL container is used. In some embodiments the container is a drop bottle or gel / ointment tube. In some embodiments, the container includes a removable sealing top for sealing the liquid container and a neck portion connecting the liquid container and the sealing top.

In some embodiments, the container is made of one or more of the following materials: polyvinyl chloride, polypropylene, polyethylene terephthalate, polyethylene terephthalate, polyethylene terephthalate G, high density polyethylene, low density polyethylene, polybutylene terephthalate, polyurethane, Polyethylene vinyl acetate, silicone, acrylonitrile butadiene styrene, polytetrafluoroethylene, polycarbonate, polystyrene, polymethylmethacrylate, polysulfone, polyvinylidene chloride, or combinations thereof. Glass containers and surfaces are provided in some embodiments that reduce the adhesion of the composition to the inner container surface.

In some embodiments, the polypeptides include Lacripep ^™ having SEQ ID NO: 1; Or a pharmaceutically acceptable salt thereof. In some embodiments, the polypeptide has a sequence selected from the group of SEQ ID NOs: 2-9, or a pharmaceutically acceptable salt, or fragment or fragment thereof. In some embodiments, the polypeptide, or pharmaceutically acceptable salt thereof, comprises at least about 80%, 85% 90%, 95%, or 98% sequence homology to SEQ ID NO: 1 or SEQ ID NO: 2-9 Has

Some embodiments provide a method of administration comprising topically applying a composition such as a liquid eye drop from a disposable container to the eye. Some embodiments provide a method of administration comprising topically applying a composition to the eye, such as sterile, unconserved liquid eye drops from a disposable container.

Some embodiments provide a method of treating dry eye and / or primary Sjogren's syndrome comprising administering a composition disclosed herein to the eye of a subject having dry eye and / or primary Sjogren's syndrome, wherein the polypeptide or a medicament thereof Academicly acceptable salts are in an amount of 0.005%, or 0.01%, and the polypeptide is Ac-Lys-Gln-Phe-Ile-Glu-Asn-Gly-Ser-Glu-Phe-Ala-Gln-Lys-Leu- A sequence consisting of Leu-Lys-Lys-Phe-Ser-NH2, wherein "Ac" represents an acetyl group, the C-terminus has the sequence to be aminated (SEQ ID NO: 1), and one droplet is the subject's eye Up to three times per day. In some embodiments, the administration is performed with fluorescein cornea in the eye of the subject at least two weeks after treatment, or at least four weeks after treatment, or at least six weeks after the start of four weeks of treatment compared to baseline measurements prior to the start of treatment. Improve staining (FCS) total rating (US National Institute for Ophthalmology 0-15 scale). In some embodiments, administration improves one or more of the following:

Dry eye after at least 2 weeks of treatment or after at least 4 weeks of treatment, compared to the criteria for the visual pain scale;

SANDE (collective score SANDE-1) after at least two weeks of treatment, compared to baseline measurements prior to initiation of treatment;

An average score for SANDE (gross score SANDE-1) after at least two weeks of treatment, compared to baseline measurements prior to initiation of treatment;

Individual symptom evaluation (immediate) after at least two weeks of treatment compared to baseline measurements prior to initiation of treatment;

Mean score for individual symptom evaluation (Reflective) after at least 2 weeks of treatment, compared to baseline measurements prior to initiation of treatment;

LGCS in the subject's eye after at least two weeks of treatment, compared to baseline measurements prior to initiation of treatment;

Anesthesia Schirmer test in the eye of the subject after at least 2 weeks of treatment, compared to baseline measurements prior to initiation of treatment;

TFBUT in the eye of the subject after at least two weeks of treatment compared to baseline measurements prior to initiation of treatment;

FCS in the eye of the subject after at least two weeks of treatment, compared to baseline measurements prior to initiation of treatment;

SANDE at 1 week after at least 2 weeks of treatment, or after at least 4 weeks of treatment, or 4 weeks of treatment compared to baseline measurements prior to initiation of treatment (overall score for SANDE 1);

Individual symptoms (immediate) at week 1 after at least 2 weeks of treatment, or after at least 4 weeks of treatment, or 4 weeks of treatment, compared to baseline measurements before initiation of treatment;

An average score for (Gross Score SANDE-2) at Week 1 after at least 2 weeks of treatment, after at least 4 weeks of treatment, or after 4 weeks of treatment, compared to baseline measurements before initiation of treatment;

An average score for individual symptom evaluation (reflective) at 1 week after at least 2 weeks of treatment, or after at least 4 weeks of treatment, or 4 weeks of treatment, compared to baseline measurements before initiation of treatment;

FCS and SANDE 1 and individual symptom assessments (immediately) after at least two weeks of treatment, or after at least four weeks of treatment, or four weeks of treatment, compared to baseline measurements before initiation of treatment;

LGCS after at least 2 weeks of treatment or after at least 4 weeks of treatment compared to baseline measurements prior to initiation of treatment;

Anesthesia Schirmer test results after at least 2 weeks of treatment or after at least 4 weeks of treatment compared to baseline measurements prior to initiation of treatment;

TFBUT at 1 week after at least 2 weeks of treatment, or after at least 4 weeks of treatment, or 4 weeks of treatment, compared to baseline measurements prior to initiation of treatment.

In some embodiments, administration of the composition to a group of subjects does not result in a statistically higher rate of side effects compared to the rate of side effects for administration of a placebo to a similar group of subjects. In some embodiments, administration of the composition to a group of subjects does not result in a statistically higher rate of severe side effects compared to the rate of side effects for administration of a placebo to a similar group of subjects. In some embodiments, the concentration of polypeptide or pharmaceutically acceptable salt thereof is about 0.005%. In some embodiments, the concentration of polypeptide or pharmaceutically acceptable salt thereof is about 0.01%. In some embodiments, the subject meets all of the following criteria:

Age 18 years or older;

Prior history or current diagnosis as documented of primary Sjogren's syndrome according to the US-European consensus group Sjogren's syndrome criteria with 4 of 6 total criteria or 3 of 4 signs;

If the subject receives systemic (oral) therapy for the treatment of Sjögren's syndrome, the subject must receive stable systemic treatment defined as the same treatment for the immediate 90 days;

Persons with a history of dry eye-related ocular symptoms, and self-recorded use of over the counter ocular humectants within the past 120 days; And

Meet all of the following criteria prior to the start of treatment:

a) Fluorescein corneal staining (FCS) total score ≧ 4 and <15 (where 0 = no staining) on the US National Eye Institute (NEI / Industry Workshop) scale;

b) score of symptom ≥40 using the SANDE questionnaire

c) anesthetized Schirmer test score of ≦ 5 mm wet / 5 min.

d) Lysamine Green Conjunctival Staining (LGCS) total score of ≧ 5 using the US National Eye Institute (NEI / Industry Workshop) scale, where 0 = no staining;

Here, the subject must meet all four criteria in at least one identical eye at the time of visit.

In some embodiments, the subject does not meet one or more of the following criteria:

Any active infectious eye condition;

Having monocular, or worse corrected visual acuity (BCVA) as assessed by corrective lenses of +1.0 logMAR or, if necessary, by the Diabetic Retinopathy Early Treatment Study (ETDRS);

Ocular inflammatory conditions not associated with dry eye syndrome (eg, conjunctivitis, keratitis, anterior blepharitis, etc.);

Clinical evidence of scarring ocular surface diseases such as scarring ocular pseudophobic or Stephen Johnson syndrome;

The use of any topical eye drops (including topical cyclosporin, and / or topical cortico-steroids) may not be stopped in the course of treatment with the composition;

Restasis® (topical ophthalmic cyclosporin) was used within 60 days prior to the start of treatment with the composition;

Xiidra® (topical ophthalmic repeat) was used within 30 to 60, or 60 days prior to the start of treatment with the composition;

The subject's eye has a fluorescein corneal staining (FCS) total score = 15 or a score = 3 on a superior area NEI / Industry Workshop scale or the subject's eye is diffuse confluent staining ), Filaments, or FCS with obvious epithelial defects;

Subjects with or having an activity of herpes keratitis within 365 days of initial treatment or receiving chronic oral antiviral agents for herpes disease;

Inability to stop and refrain from using contact lenses during the course of treatment;

Have a history of collagen vascular disease, autoimmune disease, or rheumatic disease (eg, lupus, rheumatoid arthritis, etc.) other than primary Sjogren's syndrome;

Have a current anterior membrane disorder or a history thereof;

Had corneal transplant or similar corneal surgery (DALK, DSEK, DMEK, etc.);

Used or expected use of amiodarone;

Dose or changes to the following doses are expected within 30 days prior to treatment start: tetracycline, omega 3 or omega 6;

Persons whose doses are expected to change within the 60 days prior to the start of treatment and / or for the duration of treatment or for which the following doses are expected: anticholinergics, antidepressants, oral contraceptives, isotretinoin, oral systemic corticosteroids, oral systemic immunosuppressants,

Topical ocular antihistamines, ocular, inhaled or intranasal corticosteroids, topical or oral mast cell stabilizers, oral antihistamines, topical or nasal vasoconstrictors, topical ocular NSAIDs within 30 days prior to the start of treatment and / or for the duration of the study. Topical ocular antibiotics were used;

The subject's eye had a cauterization of the punctum or a change to the (insert or remove) tear point plug (s) within the past 90 days prior to the start of treatment;

In the eye of the subject had corneal refractive surgery (LASIK, PRK, RK);

History of any surgical procedure on the ocular surface or eyelid within 365 days prior to treatment start with a history of intraocular surgery within 90 days prior to start of treatment;

Pregnant or suspected of being pregnant;

Breastfeeding or intend to breastfeed; And

Participate in a device or investigational drug study or clinical trial within 30 days of starting treatment.

In some embodiments of any of the compositions, kits or methods disclosed herein, the polypeptide is Ac-Lys-Gln-Phe-Ile-Glu-Asn-Gly-Ser-Glu-Phe-Ala-Gln-Lys-Leu-Leu A sequence consisting of -Lys-Lys-Phe-Ser-NH2, where "Ac" represents an acetyl group and the C-terminus has the sequence to be amidated (SEQ ID NO: 1). In some embodiments of any of the compositions, kits, or methods disclosed herein, the amount of polypeptide of the pharmaceutically acceptable salt thereof is 0.01% or 0.005%. In some embodiments, the comparison to the reference measurement prior to the start of treatment comprises instead or additionally the comparison of treatment with the polypeptide relative to the vehicle control. In some embodiments of any of the compositions, kits or methods disclosed herein, the composition does not contain tiloxapol. In some embodiments of any of the compositions, kits, or methods disclosed herein, the composition does not contain EDTA. In some embodiments of any of the compositions, kits or methods disclosed herein, the composition is undegraded in the composition after storage of the composition for 1 week at 5 ± 3 ° C. or 25 ± 2 ° C. and at 25 ± 5% relative humidity. At least about 99.0% polypeptide in form. In some embodiments of any of the compositions, kits or methods disclosed herein, the composition is at least about 99.0 in undissolved form in the composition after storage of the composition for 2 weeks at 25 ± 2 ° C. and 25 ± 5% relative humidity. Maintain% polypeptide. In some embodiments of any of the compositions, kits or methods disclosed herein, the composition is undegraded in the composition after storage of the composition for 1 month at 5 ± 3 ° C. or 25 ± 2 ° C. and at 25 ± 5% relative humidity. At least about 99.0% polypeptide in form. In some embodiments of any of the compositions, kits or methods disclosed herein, the composition maintains at least about 99.0% polypeptide in undigested form in the composition after storage of the composition at 5 ± 3 ° C. for 2 months. In some embodiments of any of the compositions, kits or methods disclosed herein, the composition is at least about 99.0% in undissolved form in the composition after storage of the composition for 3 months at 5 ± 3 ° C. or −20 ± 5 ° C. Maintain the polypeptide. In some embodiments of any of the compositions, kits or methods disclosed herein, the composition maintains at least about 99.0% polypeptide in undissolved form in the composition after storage of the composition at 5 ± 3 ° C. for 4 months. In some embodiments of any of the compositions, kits or methods disclosed herein, the composition maintains at least about 99.0% polypeptide in undissolved form in the composition after storage of the composition at 5 ± 3 ° C. for 5 months. In some embodiments of any of the compositions, kits or methods disclosed herein, the composition retains at least about 99.5%, 99.9%, or 99.95% polypeptide in undissolved form in the composition. In some embodiments of any of the compositions, kits or methods disclosed herein, the composition comprises at least about 80% or 90% polypeptide in undissolved form in the composition after storage of the composition at 5 ± 3 ° C. for 12 months. Keep it.

1 shows the stability of Lacripep ^™ (SEQ ID NO: 1) (0.001%) in phosphate buffered saline (PBS), pH 4.5 and 7.0. Lacripep ^™ solution was analyzed by MALDI TOF mass spectroscopy at 60 ° C. at time point 0 (top panel) and after 2 weeks (bottom panel). After 2 weeks, the peak at 993.9 (m / e) (indicated by the arrow) corresponding to the degradation product is evident due to the disappearance of the Lacripep ^™ peak in both pH 4.5 and 7.0 solutions. Additional degradation products are seen in the pH 4.5 solution at about 2270 (m / e) (indicated by arrow).
2 shows the good stability of Lacripep ^™ (SEQ ID NO: 1) (0.001%) in citrate buffer to pH 6 and 6.5. Lacripep ^™ solution was analyzed by MALDI TOF mass spectroscopy at 60 ° C. at time point 0 (top panel) and after 2 weeks (bottom panel). After 2 weeks, the intensity of the Lacripep ^TM peak (indicated by the arrow) is not changed and there is no significant increase in the lower mass relative to the charge ratio peak.

Justice

Exemplary definitions of terms used herein are as follows. Unless expressly stated otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art with respect to the entire specification. All patents, applications, publications, and other publications mentioned herein are incorporated herein by reference unless fully stated otherwise.

As used herein, the term “about” means an amount, value, number, frequency, percentage, amount, or amount that varies by +/− 10% relative to a reference amount, value, number, frequency, percentage, amount, or weight Refers to the weight.

Unless indicated otherwise, when percentage (%) values are used herein, the values refer to weight / weight percentage values.

The term "extinguishing agent" as used herein will be given in its usual sense, and its main purpose will include substances for altering the osmolarity of the composition. Suitable isotonic agents include, but are not limited to, propylene glycol, polyethylene glycol, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, monosaccharides such as dextrose, fructose, galactose, and / or simple polyols such as sugar alcohol mannitol, sorbitol, xylitol, lactitol, Isomaltitol, maltitol, hydrogenated starch hydrolyzate, glycerin, and combinations of the foregoing.

The term "stabilizer" as used herein will be given in its conventional sense and will include substances that inhibit chemical reactions with peptides. Stabilizers can include, for example, antioxidants such as sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, butylated hydroxytoluene, and combinations of the foregoing.

As used herein, the term "surfactant" will be given in its conventional sense and will include amphiphilic molecules, meaning that they contain both hydrophobic groups (tails) and hydrophilic groups (heads). . Thus, the surfactant contains both a water insoluble (or oil soluble) component and a water soluble component. Surfactants as used herein may be detergents, wetting agents, emulsifiers, blowing agents, or dispersants. In some embodiments, the polypeptide can act as a surfactant.

As used herein, the term “chelating agent” will be given in its usual sense and will include compounds capable of forming two or more bonds to metal ions, ie, multi-dentate ligands. Chelating agents include, but are not limited to, ethylenediaminetetraacetic acid (EDTA), ethylenediamine, amino acids such as glutamic acid and histidine, organic diacids such as oxalic acid, malonic acid, succinic acid and the like and pharmaceutically acceptable salts of the foregoing. In many embodiments, the chelating agent is EDTA, or a pharmaceutically acceptable salt thereof. In some embodiments, the polypeptide can act as a chelator.

The term "viscosity building agent" as used herein will be given in its conventional sense and will include substances that affect the viscosity (centifaz, or Cp) of the composition. Examples of viscosity enhancers include, but are not limited to: polysaccharides such as hyaluronic acid and salts thereof, chondroitin sulfate and salts thereof, dextran, various polymers of the cellulose series (and derivatives thereof), vinyl polymers, and acrylic acid polymers. Non-limiting examples of viscosity constituents are polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), and polyacrylic acid (PAA).

The term "ophthalmically acceptable" as used herein will be given in its usual sense and will include materials compatible with ocular tissue; That is, it does not cause a significant or excessive deleterious effect when contacted with eye tissue.

As used herein, the terms “stable,” “stable” or “stabilized” will be given in their usual sense and include products and compositions that enhance the primary, secondary and / or tertiary structure of a polypeptide. will be. In some embodiments, stabilized compositions may have an acceptable percentage of peptide degradation, or aggregation, production after a given period of time. These peptide degradation products may be the result of, for example, oxidation and / or hydrolysis of the peptides.

The terms "peptide", "polypeptide" and "protein" as used herein are used interchangeably and will be given in their conventional meanings. Unless obvious from the context, well-known terms include polymers having at least two amino acids linked through peptide bonds. Thus the term includes oligopeptides, analogs, derivatives, acetylated derivatives, glycated derivatives, pegylated derivatives and the like.

The term “pharmaceutically acceptable salts” will be given in their usual sense and includes salts of compounds that do not cause significant irritation to the organism to which they are administered, and which do not eliminate or substantially reduce the biological activity and properties of the compound. something to do. In some embodiments, salts of a compound may enhance the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting a compound with an inorganic acid such as hydrochloric acid (eg hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, or phosphoric acid. Pharmaceutical salts also include compounds and organic acids such as aliphatic or aromatic carboxyl or sulfonic acids, for example formic acid, acetic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, p It can be obtained by reacting with toluenesulfonic acid, salicylic acid or naphthalenesulfonic acid. In addition, the pharmaceutical salts may react with a compound and a base to form salts, ammonium salts, alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as calcium or magnesium salts, salts of organic bases such as dicyclohexylamine, N-methyl- It can be obtained by forming salts with D-glucamine, tris (hydroxymethyl) methylamine, C ₁ -C ₇ alkylamine, cyclohexylamine, triethanolamine, ethylenediamine, and amino acids such as arginine and lysine. In some embodiments, the polypeptide is an acetate salt.

Advantages in Many Embodiments

As described above and herein, many embodiments of the present application provide compositions that are stable at room temperature. In many embodiments, the composition has reduced levels of stabilizers and other additives that can cause unwanted side effects and still provide the desired stability. In some embodiments, the composition provides stability in the eye, nasal cavity, mouth, epithelium and other tissues for up to 1, 3, 6, 12, 24 and 48 hours. In some embodiments, the composition does not evaporate, absorb, vent or otherwise remove some or all of the components after application to the eye or other areas, instead for several hours (eg, 1-3 hours, 3 -6 hours, 6-12 hours, 12-24 hours and within) formulated to remain stable and active. In some embodiments, the composition comprises a peptide, such as Lacripept ^™ or other sequences identified herein, wherein the peptide is applied to the eye, and the peptide is applied to the lipid layer of the eye gate covering the eye, or to the lipid of the tear Integrated at the interface of the aqueous component, the peptide stabilizes the tear and remains in the tear for a period of at least 1-3 hours, at least 3-6 hours, or at least 12-24 hours, or more than 24 hours. This feature is particularly advantageous in many embodiments because it allows the active ingredient (such as the peptide) to remain stable and effective for long periods of time. In some embodiments, the reduced frequency of administration reduces the overall overall burden of ingredients on sensitive parts of the body (such as the eye).

While peptides are provided in many embodiments herein, other compounds may be used as active ingredients in addition to or instead of peptides.

Peptides are highly selective and potent, while at the same time relatively safe and well tolerated. Peptides are particularly well suited for the compositions described herein because the peptides may be chemically and physically unstable relative to certain small molecule-based therapeutics. For example, peptides tend to be easily hydrolyzed, oxidized, and aggregated. Polypeptide compositions are typically aqueous solutions containing the active peptide in combination with a number of stabilizers, preservatives, and other agents to maintain the efficacy of the peptide. Stabilizers, preservatives, and other agents may maintain the chemical and / or structural integrity of the polypeptide and thus preserve its efficacy. Certain additives such as stabilizers and preservatives can cause undesirable side effects including hypersensitivity reactions, pruritis, and puncture or burning. However, in order to maximize shelf life and maintain efficacy of the peptides, these additives are needed in most peptide compositions in amounts that cause undesirable consequences. Even in compositions with all these additives, the peptide therapeutics typically have to be refrigerated, which makes transportation difficult, even when using refrigeration, it has a short shelf life. Furthermore, since the peptides decompose and / or aggregate over time (particularly through warming and cooling, especially when selected for use at room temperature from cold storage), the by-products may not be inert, which may be toxic and / or immunogenic. Can be. Formulations may be attempted to increase the potency of the peptide composition by increasing the amount of active peptide in the composition. However, increased peptide concentration also increases the rate of inactivation and peptide aggregation.

Thus, many embodiments herein provide peptides that provide a therapeutic amount of a peptide, that are stable at room temperature, and that contain reduced (eg, only trace amounts) of stabilizers and / or preservatives or none at all. To provide a composition.

In some embodiments, the peptide is selected from the group consisting of: (a) amino acid sequence KQFIENGSEFAQKLLKKFS, Ac-KQFIENGSEFAQKLLKKFS-NH ₂ , or Ac-Lys-Gln-Phe-Ile-Glu-Asn-Gly-Ser-Glu- Phe-Ala-Gln-Lys-Leu-Leu-Lys-Lys-Phe-Ser-NH ₂ , where "Ac" represents an acetyl group and the C-terminus is amidated (SEQ ID NO: 1), which is also referred to herein as " Referred to as lacripept ^TM "; And (b) amino acid sequence KQFIENGSEFAQKLLKKFSLLKPWA, Ac-KQFIENGSEFAQKLLKKFSLLKPWA-NH ₂ , or Ac-Lys-Gln-Phe-Ile-Glu-Asn-Gly-Ser-Glu-Phe-Ala-Gln-Lys-Leu-Leu-Leu-Leu-Leu-Leu-Leu-Leu-Leu-Leu-Leu-Leu-Leu-Leu-Leu-Lu Lys-Phe-Ser-Leu-Leu-Lys-Pro-Trp-Ala-NH ₂ , where "Ac" represents an acetyl group and the C-terminus is amidated (SEQ ID NO: 2). In another embodiment, the peptide has one of the following amino acid sequences, or fragments thereof, optionally having acetylated N-terminus and / or amidated C-terminus:

In many embodiments, the peptide has the amino acid sequence Ac-KQFIENGSEFAQKLLKKFS-NH ₂ or Ac-Lys-Gln-Phe-Ile-Glu-Asn-Gly-Ser-Glu-Phe-Ala-Gln-Lys-Leu-Leu-Lys -Lys-Phe-Ser-NH ₂ , wherein "Ac" represents an acetyl group and the C-terminus is amidated (SEQ ID NO: 1). In In some embodiments, the peptide is Lacripep ^™ . In some embodiments, the peptide is any one or more of SEQ ID NOs: 1-9.

Buffer and pH

The buffer stabilizes the pH of the solution when acidic or alkaline substances are added to the solution, i.e. withstands changes in pH. Suitable buffers for use in the compositions include, but are not limited to, glycine hydrochloride, sodium acetate, phosphate buffered saline (PBS) (including mono- and dihydrogen phosphate salts), citrate buffers (citric acid and sodium citrate), phosphates Citrate buffer, tris (hydroxymethyl) aminomethane (Tris), carbonate buffers (sodium carbonate and sodium bicarbonate), borate buffers, and combinations thereof.

In some embodiments, the buffer comprises one or more of sodium acetate, phosphate buffered saline (PBS), citrate buffers (citric acid and sodium citrate), and phosphate-citrate buffers. In some embodiments, the buffer is selected from the group consisting of sodium acetate, phosphate buffered saline (PBS), citrate buffers (citric acid and sodium citrate), and phosphate-citrate buffers.

In some embodiments, the amount of buffer is limited to a range defined by less than 0.1, 0.2, 0.3, or 0.4% or any two of the above values.

In one embodiment, the buffer is citrate buffer (citric acid and sodium citrate). In one embodiment, the only buffer is citrate buffer and no other buffer is present in the composition.

In some embodiments, the pH of the composition is 6-7.4; 6.1 to 7.3; 6.2 to 7.2; 6.3 to 7.1; 6.4 to 7.0; 6.5 to 6.9; 6.6 to 6.8; Or any pH between them.

In some embodiments, the pH of the composition is 6; 6.1; 6.2; 6.3; 6.4; 6.5; 6.6; 6.7; 6.8; 6.9; 7; 7.1; 7.2; 7.3; 7.4, or a range defined by any two, or an approximation thereof.

In some embodiments, the pH of the composition is 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, or 6.8, or an approximation thereof.

The pH of the composition can be adjusted as needed by the addition of a solution of acid or base. Any acid or base whose conjugate is ophthalmically acceptable can be used. Acids include, for example, hydrochloric acid, and bases include, for example, sodium and potassium hydroxide.

Chelating agents

In some embodiments, the composition further comprises one or more chelating agents. In some embodiments, the chelating agent is ethylenediaminetetraacetic acid, edetate disodium (EDTA), ethylenediamine, amino acids such as glutamic acid and histidine, organic diacids such as oxalic acid, malonic acid, succinic acid, and the like, 3-dimercaptopropanesulphate Phonic acid (DMPS), alpha lipoic acid (ALA), 2,3-dimercaptopropanesulfonic acid (DMPS), thiamine tetrahydrofurfuryl disulfide (TTFD), penicylamine, dimercaptosuccinic acid (DMSA), combinations thereof, And pharmaceutically acceptable salts of the above.

In some embodiments, the chelating agent, by way of non-limiting example, EDTA, or a pharmaceutically acceptable salt thereof, is 0.0001% to 0.1%; 0.0005% to 0.05%; 0.0006% to 0.04%; 0.0007% to 0.003%; 0.0008% to 0.002%; 0.0009% to 0.001%; Or within any value contained within or within the range thereof. In some embodiments, the chelating agent is 0.1%; 0.09%; 0.08%; 0.07%; 0.06%; 0.05%; 0.04%; 0.03%; 0.02%; 0.01%; 0.009%; 0.008%; 0.007%; 0.006%; 0.005%; 0.004%; 0.003%; 0.002%; 0.001%; 0.0009%; 0.0008%; 0.0007%; 0.0006%; 0.0005%; 0.0004%; 0.0003%; 0.0002%; Or in an amount of 0.0001%, or less, or in a range defined by any two of the above values.

In some embodiments, the chelating agent, such as EDTA, or a pharmaceutically acceptable salt thereof, is present at less than about 0.05% or less than about 0.005% (eg, about 0.001%).

Stabilizer

Buffers and chelators can stabilize the peptide component of the composition by maintaining pH and reducing metal ion mediated degradation of the peptide. In some embodiments, the composition further comprises one or more peptide stabilizers in addition to the buffer and / or chelating agent. In some embodiments, one or more stabilizers other than buffers and / or chelating agents are disaccharides, polysaccharides (eg hyaluronic acid), polyols, sugar alcohols, amino acids, proteins (eg serum albumin), and combinations thereof It is selected from the group consisting of. In some embodiments, non-limiting examples of stabilizers include trehalose, sucrose, mannitol, sorbitol, polysorbate 20, polysorbate 80, histidine, glycine, and arginine, and combinations thereof. In one embodiment, the composition does not include stabilizers other than buffers and / or chelators.

Polypeptide Degradation

Polypeptides tend to be easy for physical and chemical degradation, eg, aggregation, shearing, oxidation, deamidation, and hydrolysis. In fact, liquid peptide compositions have a high risk for physical and chemical instability in the manufacturing and storage process. Reducing polypeptide degradation is particularly important for diluted peptide formulations, which initially contain very small amounts of specific peptides. Even the loss of even the smallest of the initial small amounts has a significant impact on the efficacy of the composition.

In some embodiments, composition stability is determined by high-performance liquid chromatography (HPLC). In some embodiments, composition stability is determined by high-performance liquid chromatography-mass spectroscopy (HPLC-MS).

In some embodiments, the composition stability is such that the sealed container of the composition may contain days, weeks or months (eg, 1-24 days or months, eg, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 days or months), left in the dark at room temperature or determined after exposure to light do.

In some embodiments, the composition stability is such that the sealed container of the composition may be days, weeks or months (eg 1-24 days or months, eg, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 days or months) 2-8 ° C., for example 5 ° C., or between them. It is determined after it has been left in the dark at any temperature of or has been exposed to light.

In some embodiments, the composition stability is such that the sealed container of the composition may be days, weeks or months (eg, 1-24 days or months, eg, 1, 2, 3, 4, 5, 6, 7, 8 , 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 days or months) -10 to -30 ° C, for example -25 ° C Or after being exposed to light or left in the dark at a temperature of any value between them.

In some embodiments, the composition stability is such that the sealed container of the composition is at a temperature of 2-8 ° C. (storage) at room temperature for 5 minutes 1, 2 or 3 times per day for 1-60 days, or any temperature therebetween. It is placed in the dark room or exposed to light and determined after extraction.

In some embodiments, the composition comprises an initial amount of the polypeptide, or a pharmaceutically acceptable salt thereof, in intact, non-digested or non-aggregated form after exposure to one or more of the conditions described herein above. Or at least 99.99%, 99.95%, 99.9%, 99% of the activity; 98%; 97%; 96%; 95%; 94%; 93%; 92%; 91%; 90%; 89%; 88%; 87%; 86%; 85%; 84%; 83%; 82%; 81%; 80%; 79%; 78%; 77%; 76%; 75%; 74%; 73%; 72%; 71%; 70%; Or provide a value between them. In one embodiment, the amount or activity of the intact polypeptide, or pharmaceutically acceptable salt thereof, is at least 80%, 85%, 90% or 95% of the initial amount. In some embodiments, the amount or activity of the intact polypeptide, or pharmaceutically acceptable salt thereof, is at least 97% of the initial amount.

In some embodiments, the composition comprises 30% after exposure to one or more of the conditions described above and herein; 29%; 28%; 27%; 26%; 25%; 24%; 23%; 22%; 21%; 20%; 19%; 18%; 17%; 16%; 15%; 14%; 13%; 12%; 11%; 10%; 9%; 8%; 7%; 6%; 5%; 4%; 3%; 2%; Peptide aggregation products or peptide degradation products within the range defined by 1% or less, or any two. In some embodiments, the composition comprises up to about 15%, or up to 20% of inactive peptides.

In some embodiments, the composition comprises 30% after exposure to one or more of the conditions described above and herein; 29%; 28%; 27%; 26%; 25%; 24%; 23%; 22%; 21%; 20%; 19%; 18%; 17%; 16%; 15%; 14%; 13%; 12%; 11%; 10%; 9%; 8%; 7%; 6%; 5%; 4%; 3%; 2%; A total amount of peptide degradation products and peptide aggregation products within the range defined by 1% or less, or any two.

In some embodiments, the composition comprises a very low level of buffer in combination with a very low level of chelator. In some embodiments, the buffer is citrate buffer and the chelator is EDTA. The combination of low levels of citrate buffer (eg, 0.012% to 0.020%) and EDTA (eg, 0.0005% to 0.005%) contains low levels of peptide (eg, 0.001 to 0.01%). It offers surprising and unexpected advantages of stabilizing the composition. Such stabilized compositions provide advantages in the manufacture, transport, storage, and use of peptide compositions by reducing peptide aggregation and degradation, thereby maintaining the efficacy of the peptide composition and reducing the buildup of unwanted degradation products in the composition. to provide.

In some embodiments, stabilized compositions reduce the rate of degradation and / or formation of aggregated products.

In some embodiments, the peptide is Lacripept ^™ . In some embodiments, the stabilized composition comprises less than about 5%, 4%, 3%, 2%, or about 1% total decomposition product. In some embodiments, the stabilized composition comprises no more than 0.25%, 0.5%, 0.75%, 1.0%, 1.25%, 1.5%, 1.75%, or 2.0% of any single decomposition product. In some embodiments, the stabilized composition comprises less than about 5%, 4%, 3%, 2%, or about 1% total degradation product and 0.25%, 0.5%, 0.75%, 1.0%, 1.25%, 1.5%, Up to 1.75%, or 2.0% of any single decomposition product.

In some embodiments, the aggregation product comprises dimers, trimers, tetramers, or larger-sized peptide aggregates.

Preservative

In some embodiments, the composition further comprises one or more preservatives to prevent the growth of microorganisms in the composition. In some embodiments, the composition further comprises one or more preservatives to maintain sterility of the composition. In some embodiments, the composition further comprises one or more preservatives to prevent the growth of microorganisms and to maintain the sterilization of the composition. However, in many embodiments, preservatives are provided in reduced amounts. In some embodiments, the one or more preservatives are benzalkonium chloride, cetylpyridinium chloride, chlorobutanol, benzododecinium bromide, methylparaben, propylparaben, phenylethyl alcohol, sodium perborate, edentate disodium, chlorobutanol, Sorbic acid, benzethonium chloride, sodium acetate, polyquaternium-1, phenylmercury nitrate, phenylmercury borate, sodium propionate, chlorhexidine, thimerosal, and combinations thereof. In some embodiments, the composition does not contain a preservative. In some embodiments, the composition does not contain detectable levels of preservatives. In some embodiments, the polypeptide may be self-preserved, ie no additional preservative is needed to maintain the sterility of the composition.

In some embodiments, the preservative is 0.0001% to 1%; 0.01% to 0.9%; 0.05% to 0.8%; 0.1% to 0.7%; 0.2% to 0.3%; 0.4% or 0.5%, or any value contained between them. In some embodiments, the preservative is 1%; 0.9%; 0.8%; 0.7%; 0.6%; 0.5%; 0.4%; 0.3%; 0.2%; 0.1%; 0.09%; 0.08%; 0.07%; 0.06%; 0.05%; 0.04%; 0.03%; 0.02%; 0.01%; 0.009%; 0.008%; 0.007%; 0.006%; 0.005%; 0.004%; 0.003%; 0.002%; Or in an amount of 0.001%, or less, or in a range defined by any two.

In some embodiments, the composition is sterile. In some embodiments, the composition is prepared from sterile components in a sterile environment. In some embodiments, the composition is sterilized immediately before packaging. In some embodiments, the composition further comprises: (1) addition of one or more quaternary ammonium chloride to the composition; (2) exposing the composition to ionizing radiation; (3) filtering the composition; (4) exposing the composition to ionizing radiation after packaging; And sterilized by one or more of any combination of the foregoing. In some embodiments, filtration includes passing the composition through a filter (including but not limited to a 0.22 micron filter to polyvinyldifluoride or other suitable membrane (eg, polyethersulfone)).

In some embodiments, the peptide is provided in bacteriostatic and / or sterile amounts. In some embodiments, the amount of peptide provided in the composition is bacteriostatic and / or sterile when one, two or three drops of the composition are administered to the surface of the eye. In some embodiments, the peptide is bacteriostatic and / or sterile against Gram-positive and / or Gram-negative bacteria, for example when administered to the eye. In some embodiments, the amount of peptide in the composition is at least 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% relative to the control composition free of peptides in surface bacteriological assays. It is enough to suppress bacterial growth. In some embodiments, the bacteria in the surface assay are selected from P. aeruginosa , E. coli , S. epidermis, S. aures , or a combination thereof. In some embodiments, the bacteriological assay is a bacterial growth assay, SYTOX Green assay, well diffusion assay, liquid medium or agar dilution assay, time-kill test, antimicrobial Gradient assay, ATP-bioluminescence assay, or propidium-iodide flow cytometry assay. In some embodiments, the peptides provided in bacteriostatic and / or sterile amounts are Lacripept ^™ .

In some embodiments, the bacteriological assay is a USP Section assay or an FDA-mandated assay. For example, the original product vessel contains the peptide solution, and each vessel is prepared and standardized inoculum (e.g., P. aeruginosa , E. coli , S. epidermis , S. aures , Or a combination thereof) and mix. The volume of the suspension inoculum should be about 0.5% to 1.0% of the volume of the product, and the concentration of the test formulation immediately after inoculation (e.g. by plate count method, or other microbial enumeration test) As measured) from 1 × 10 ⁵ to 1 × 10 ⁶ colony forming organisms (CFU) per mL of product.

Inoculated containers are incubated between 22.5 ± 2.5 ° C. in a controlled environment and sampled at specific intervals, eg, 7, 14, and 28 days. Any change in appearance is recorded and CFU / mL is determined at each sampling time point. Changes in log ₁₀ values of CFU / mL give a change over time with respect to log reduction. The product shows a log reduction of at least 1.0 from the initial calculated value at 7 days for the bacteria, a log decrease of 3.0 or less from the calculated value at the 14 days, and no increase from 14 days at 28 days, and yeast and Provides no increase from the initial number of molds. In some embodiments, the peptide provided in the bacteriostatic and / or sterile amount is Lacripept ^™ .

Surfactants

In some embodiments, the composition further comprises one or more surfactants. In some embodiments, the one or more surfactants are selected from detergents, wetting agents, emulsifiers, blowing agents, dispersants, and combinations thereof.

In some embodiments, the surfactant is an anionic surfactant. Anionic surfactants contain anionic functional groups at their heads such as sulfates, sulfonates, phosphates, and carboxylates. In some embodiments, the surfactant is a sulfate, sulfonate, or phosphate ester, for example sulfate ester. In some embodiments, the surfactant is selected from the group comprising or consisting of ammonium lauryl sulfate and sodium lauryl sulfate, such as sodium lauryl sulfate (also called SDS, sodium dodecyl sulfate). In some embodiments, the surfactant is an alkyl-ether sulfate selected from the group comprising or consisting of sodium laureth sulfate (also known as sodium lauryl ether sulfate), and sodium myreth sulfate. In some embodiments, the surfactant is a docusate such as dioctyl sodium sulfosuccinate, perfluorooctanesulfonate (PFOS), perfluorobutanesulfonate, linear alkylbenzene sulfonate (LAB). In some embodiments, the surfactant may be a carboxylate, such as an alkyl carboxylate (soap), such as sodium stearate; Sodium lauroyl sarcosinate and carboxylate-based fluorosurfactants such as perfluorononanoate, perfluorooctanoate (PFOA or PFO). In some embodiments, the polypeptides contribute to the surfactant properties of the composition.

In some embodiments, the surfactant is a cationic surfactant, such as a primary, secondary or tertiary amine, such as octenidine dihydrochloride, whose changes may be pH dependent; Or permanently charged quaternary ammonium cations such as alkyltrimethylammonium salts such as cetyl trimethylammonium bromide (CTAB) or cetyl trimethylammonium chloride (CTAC); Cetylpyridinium chloride (CPC); Benzalkonium chloride (BAC); Benzethonium chloride (BZT); 5-bromo-5-nitro-1,3-dioxane; Dimethyldioctadecyl ammonium chloride; Or dioctadecyldimethylammonium bromide (DODAB). In some embodiments, the surfactant is a zwitterionic surfactant (ie, has both cationic and anionic centers attached to the same molecule). The cationic moiety can be based on primary, secondary, or tertiary amine or quaternary ammonium cations. Anionic moieties may be more variable and include sulfonates as in CHAPS (3-[(3-colamidopropyl) dimethylammonio] -1-propanesulfonate). Other anionic groups include sultaines exemplified by cocamidopropyl hydroxylsultaine; Betaines such as cocamidopropyl betaine; Phosphates such as lecithin. In some embodiments, the surfactant can be a non-ionic surfactant (not charged).

Many long chain alcohols exhibit some surfactant properties and in some embodiments are provided herein as part of a composition. Fatty alcohol cetyl alcohol, stearyl alcohol, and cetostearyl alcohol (mainly consisting of cetyl and stearyl alcohol), and oleyl alcohol are the dominant among them. Other surfactants include cocamide MEA, cocamide DEA, dodecyldimethylamine oxide, and polyethoxylated tallow amines (POEA). Examples of non-ionic surfactants include polyoxyethylene glycol alkyl ethers such as octaethylene glycol monododecyl ether or pentaethylene glycol monododecyl ether; Polyoxypropylene glycol alkyl ethers; Glucoside alkyl ethers such as decyl glucoside, lauryl glucoside, or octyl glucoside; Polyoxyethylene glycol octylphenol ethers such as Triton X-100; Polyoxyethylene glycol alkylphenol ethers such as nonoxynol-9; Glycerol alkyl esters such as glyceryl laurate; Polyoxyethylene glycol sorbitan alkyl esters (polysorbates); Sorbitan alkyl esters (Spans); Block copolymers of polyethylene glycol and polypropylene glycol, or poloxamer.

In some embodiments, the composition may contain one or more components found in artificial tears in amounts known in the art, including but not limited to: carboxymethyl cellulose, polyvinyl alcohol, hydroxypropyl methylcellulose ( Also referred to as HPMC or hypromellose), hydroxypropyl cellulose, hydroxyethyl cellulose (HEC), and hyaluronic acid (also referred to as hyaluronan, HA), and combinations thereof. In some embodiments, the composition does not contain any of the artificial tear components.

In some embodiments, the surfactant is another peptide or protein. In some embodiments, by way of non-limiting example, the surfactant is human serum albumin. In some embodiments, another non-limiting example of surfactant is Lacripep ^™ .

In many embodiments, the surfactant is thioxapol (formaldehyde; oxirane; 4- (2,4,4-trimethylpentan-2-yl) phenol). In one embodiment, the only surfactant is thiloxapol and no other surfactant agent is present in the composition.

In many embodiments, surfactants include, but are not limited to, from 0.01% to 1% of tiloxapol; 0.05% to 0.9%; 0.1% to 0.8%; 0.2% to 0.7%; 0.3% to 0.6%; 0.4% or 0.5%, or any value contained therein. In some embodiments, the surfactant is 1%; 0.9%; 0.8%; 0.7%; 0.6%; 0.5%; 0.4%; 0.3%; 0.2%; 0.1%; 0.09%; 0.08%; 0.07%; 0.06%; 0.05%; 0.04%; 0.03%; 0.02%; 0.01%; 0.009%; 0.008%; 0.007%; 0.006%; 0.005%; 0.004%; 0.003%; 0.002%; Or in an amount of 0.001%, or less, or in a range defined by any two.

In some embodiments, the composition does not contain a surfactant. In some embodiments, the composition does not contain detectable levels of surfactant.

Isotonic and Osmolarity

In some embodiments, the composition further comprises one or more isotonic agents. Such isotonic agents are other than any buffer or polypeptide or buffer having an isotonic-modifying effect. In some embodiments, the one or more isotonic agents are propylene glycol, polyethylene glycol, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, monosaccharides such as dextrose, fructose, galactose, and / or simple polyols such as sugar alcohol mannitol, sorbitol, xylitol, lactate Thitol, isomaltitol, maltitol, hydrogenated starch hydrolyzate, glycerin, and combinations thereof.

In some embodiments, the one or more isotonic agents are selected from sodium chloride, potassium chloride, magnesium chloride, calcium chloride, dextrose, mannitol, and combinations thereof.

In some embodiments, the tonicity agent is sodium chloride. In some embodiments, sodium chloride is 0.01% to 1%; 0.05% to 0.9%; 0.1% to 0.8%; 0.2% to 0.75%; 0.3% to 0.7%; 0.4% to 0.6%; Or any value contained therein. In some embodiments, sodium chloride is 1%; 0.95%; 0.9%; 0.85%; 0.8%; 0.75%; 0.7%; 0.65%; 0.6%; 0.55%; 0.5%; 0.45%; 0.4%; 0.35%; 0.3%; 0.25%; 0.2%; 0.15%; 0.1%; 0.09%; 0.08%; 0.07%; 0.06%; 0.05%; 0.04%; 0.03%; 0.02%; Or in an amount of 0.01% or an approximation thereof; Or within the range defined by any two.

In some embodiments, the only isotonicity agent is sodium chloride and no other isotonicity agent is contained in the composition.

In some embodiments, tonicity agents, such as but not limited to sodium chloride, are added to the composition to adjust the osmolality to the desired level. In some embodiments, the osmolarity of the composition is about 150 to about 400 mOsm / kg; About 170 to about 380 mOsm / kg; About 190 to about 360 mOsm / kg; About 210 to about 340 mOsm / kg; About 230 to about 320 mOsm / kg; About 250 to about 300 mOsm / kg; About 270 to about 280 mOsm / kg; Or any value between them. In some embodiments, the osmolarity of the composition is about 250 to about 350 mOsm / kg; About 260 to about 340 mOsm / kg; About 270 to about 330 mOsm / kg; About 280 to about 320 mOsm / kg; About 290 to about 310 mOsm / kg; Or any value between them.

In some embodiments, the osmolarity of the composition is 150 mOsm / kg; 160 mOsm / kg; 170 mOsm / kg; 180 mOsm / kg; 190 mOsm / kg; 200 mOsm / kg; 210 mOsm / kg; 220 mOsm / kg; 230 mOsm / kg; 240 mOsm / kg; 250 mOsm / kg; 260 mOsm / kg; 270 mOsm / kg; 280 mOsm / kg; 290 mOsm / kg; 300 mOsm / kg; 310 mOsm / kg; 320 mOsm / kg; 330 mOsm / kg; 340 mOsm / kg; Or 350 mOsm / kg, or an approximation thereof, or within a range defined by any two.

In some embodiments, the osmolarity of the composition is about 280 mOsm / kg to about 320 mOsm / kg. In one embodiment, the osmolarity of the composition is about 300 mOsm / kg. In some embodiments, NaCl is used to adjust the osmolarity of the solution to the desired level. In one embodiment, the composition is isotonic or approximately isotonic with human tears.

Polypeptides and Other Ingredients

In some embodiments, the polypeptide, or pharmaceutically acceptable salt thereof, comprises 10 to 150 amino acids; 10 to 50 amino acids; 100 to 150 amino acids; 30 to 70 amino acids; Or any number contained therein. In some embodiments, the polypeptide, or pharmaceutically acceptable salt thereof, comprises 10 to 30 amino acids; 11 to 29 amino acids; 12 to 28 amino acids; 13 to 27 amino acids; 14 to 26 amino acids; 15 to 25 amino acids; 16 to 24 amino acids; 17 to 23 amino acids; 18 to 22 amino acids; 19 to 21 amino acids; Or any number contained therein. In some embodiments, the polypeptide, or pharmaceutically acceptable salt thereof, is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, Amino acids in the range defined as 45, 46, 47, 48, 49, or 50 or an approximation or any two.

In some embodiments, the C-terminus of the polypeptide, or pharmaceutically acceptable salt thereof, is amidated. In some embodiments, the N-terminus of the polypeptide, or pharmaceutically acceptable salt thereof, is acetylated. In some embodiments, the side chains of one or more of the polypeptides, or pharmaceutically acceptable salts thereof, are acetylated. In some embodiments, the side chains of one or more of the polypeptides, or pharmaceutically acceptable salts thereof, are amidated. In some embodiments, the N-terminus of the polypeptide, or pharmaceutically acceptable salt thereof, is acetylated and the C-terminus of the polypeptide, or pharmaceutically acceptable salt thereof, is amidated.

In some embodiments, the polypeptide, or pharmaceutically acceptable salt thereof, comprises the amino acid sequence: Ac-Lys-Gln-Phe-Ile-Glu-Asn-Gly-Ser-Glu-Phe-Ala-Gln-Lys-Leu- Leu-Lys-Lys-Phe-Ser-Leu-Leu-Lys-Pro-Trp-Ala-NH ₂ (SEQ ID NO: 2) comprises, consists of, or consists essentially of, wherein "Ac" An acetyl group and the C-terminus is amidated (represented by "NH ₂ "). In some embodiments, the polypeptide, or pharmaceutically acceptable salt thereof, comprises the amino acid sequence: Ac-Lys-Gln-Phe-Ile-Glu-Asn-Gly-Ser-Glu-Phe-Ala-Gln-Lys-Leu- Leu-Lys-Lys-Phe-Ser-NH ₂ (SEQ ID NO: 1), wherein "Ac" represents an acetyl group and the C-terminus is amidated (represented by "NH ₂ "). In some embodiments, the polypeptide, or pharmaceutically acceptable salt thereof, comprises, consists of, or essentially consists of a sequence selected from the group of SEQ ID NOs: 3-9, a fragment thereof, or a pharmaceutically acceptable salt thereof. Is done.

In some embodiments, the amount of polypeptide, or pharmaceutically acceptable salt thereof, in the composition is 0.0001% to 1%; 0.0005% to 0.5%; 0.001% to 0.1%; 0.005% to 0.05%; 0.006% to 0.04%; 0.007% to 0.03%; 0.008% to 0.02%; Or 0.009% to 0.01% or an approximation thereof. In one embodiment, the polypeptide, or pharmaceutically acceptable salt thereof, is present in the composition at about 0.003% to 0.09% (eg, 0.005%, 0.01%, 0.02%, 0.03% and ranges thereof).

In some embodiments, the polypeptide, or pharmaceutically acceptable salt thereof, is 0.0001, 0.00025, 0.0005, 0.00075, 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.010, 0.011, 0.012, 0.013 , 0.014, 0.015, 0.020, 0.030, 0.040, 0.050, 0.060, 0.070, 0.080, 0.090, 0.10, 0.20, 0.30, 0.40, 0.50, 0.60, 0.70, 0.80, 0.90, or 1.0%, approximation, greater than or equal to Present in the composition in an amount less than or in an amount defined by any two.

In some embodiments, the composition comprises about 0.001% to about 0.05% of a polypeptide, such as Lacripept ^™ or other peptides identified herein, or a pharmaceutically acceptable salt thereof; About 0.001% to about 0.015% citric anhydride; About 0.02% to about 0.40% sodium citrate dihydrate; About 0.0005% to about 0.005% disodium EDTA; Sterile aqueous composition comprising, consisting of, or consisting essentially of about 0.005% to about 0.15% of tiloxapol, and optionally, about 0.005% to about 0.1% methylparaben; The pH of the composition is adjusted using NaOH or HCl to be about 6.2 pH to about 6.8 pH, and the osmolarity of the composition is adjusted using NaCl to be about 250 to about 350 mOsm / kg. In some embodiments, the amount of NaCl is about 0.1% to about 1%. In one embodiment, the composition does not comprise methylparabens. In one embodiment, the composition consists only of the ingredients listed and any additional active ingredients, excipients (eg, viscosity constituents, buffers, chelating agents, stabilizers, preservatives, surfactants, and isotonic agents) Contains no carriers or diluents.

In some embodiments, the composition comprises about 0.01% ± 0.001% of a polypeptide, such as Lacripept ^™ or other peptides identified herein, or a pharmaceutically acceptable salt thereof; About 0.0098% ± 0.001% citric anhydride; About 0.279% ± 0.028% sodium citrate dihydrate; About 0.001% ± 0.0001% of disodium EDTA; A sterile aqueous composition comprising, consisting of, or consisting essentially of about 0.05% ± 0.005% of tiloxapol, about 0.04% ± 0.004% of methylparaben; Wherein the pH of the composition is adjusted using NaOH or HCl to be about 6.2 to about 6.8, and the osmolarity of the composition is adjusted using NaCl to be about 250 to about 350 mOsm / kg. In some embodiments, the amount of NaCl is about 0.50% ± 0.05%. In one embodiment, the composition does not comprise methylparabens.

In some embodiments, the composition comprises about 0.005% ± 0.0005% of a polypeptide, such as Lacripept ^™ or other peptides identified herein, or pharmaceutically acceptable salts thereof; About 0.0098% ± 0.001% citric anhydride; About 0.279% ± 0.028% sodium citrate dihydrate; About 0.001% ± 0.0001% of disodium EDTA; A sterile aqueous composition comprising, consisting of, or consisting essentially of about 0.05% ± 0.005% of tiloxapol, about 0.04% ± 0.004% of methylparaben; Wherein the pH of the composition is adjusted using NaOH or HCl to be about 6.2 to about 6.8, and the osmolarity of the composition is adjusted using NaCl to be about 250 to about 350 mOsm / kg. In some embodiments, the amount of NaCl is about 0.50% ± 0.05%. In one embodiment, the composition does not comprise methylparabens.

In some embodiments, the composition comprises about 0.001% ± 0.0001% of a polypeptide, such as Lacripept ^™ or other peptides identified herein, or a pharmaceutically acceptable salt thereof; About 0.0098% ± 0.001% citric anhydride; About 0.279% ± 0.028% sodium citrate dihydrate; About 0.001% ± 0.0001% of disodium EDTA; A sterile aqueous composition comprising about 0.05% ± 0.005% of tiloxapol, about 0.04% ± 0.004% of methylparaben; Wherein the pH of the composition is adjusted using NaOH or HCl to be about 6.2 to about 6.8, and the osmolarity of the composition is adjusted using NaCl to be about 250 to about 350 mOsm / kg. In some embodiments, the amount of NaCl is about 0.50% ± 0.05%. In one embodiment, the composition does not comprise methylparabens.

In some embodiments, including but not limited to, the sterile composition, the polypeptide is Lacripept ^™ having SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the polypeptide is a polypeptide having SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof. In some embodiments, the polypeptide is a polypeptide having a sequence selected from the group of SEQ ID NOs: 3-9, or a pharmaceutically acceptable salt or fragment or fragment thereof.

In some embodiments, including but not limited to, the sterile composition, the pH of the composition is about 6.5 to about 6.6.

In some embodiments, including but not limited to, the sterile composition, the osmolality of the composition is from about 280 to about 320 mOsm / kg. In some embodiments, the osmolarity of the composition is about 300 mOsm / kg.

In some embodiments, the composition comprises about 0.01% ± 0.001% of Lacripepe ^TM (SEQ ID NO. 1) or other peptides identified herein; About 0.0098% ± 0.001% citric anhydride; About 0.279% ± 0.028% sodium citrate dihydrate; About 0.001% ± 0.0001% of disodium EDTA; A sterile aqueous composition comprising about 0.05% ± 0.005% of tiloxapol; Wherein the pH of the composition is adjusted using NaOH or HCl to be about 6.2 to about 6.8, and the osmolarity of the composition is adjusted using NaCl to be about 250 to about 350 mOsm / kg. In some embodiments, the amount of NaCl is about 0.50% ± 0.05%.

In some embodiments, the composition comprises about 0.005% ± 0.0005% Lacripeppe ^TM (SEQ ID NO. 1) or other peptides identified herein; About 0.0098% ± 0.001% citric anhydride; About 0.279% ± 0.028% sodium citrate dihydrate; About 0.001% ± 0.0001% of disodium EDTA; A sterile aqueous composition comprising about 0.05% ± 0.005% of tiloxapol; Wherein the pH of the composition is adjusted using NaOH or HCl to be about 6.2 to about 6.8, and the osmolarity of the composition is adjusted using NaCl to be about 250 to about 350 mOsm / kg. In some embodiments, the amount of NaCl is about 0.50% ± 0.05%.

In some embodiments, the composition comprises about 0.001% ± 0.0001% of Lacripepe ^TM (SEQ ID NO. 1) or other peptides identified herein; About 0.0098% ± 0.001% citric anhydride; About 0.279% ± 0.028% sodium citrate dihydrate; About 0.001% ± 0.0001% disodium EDTA; Sterile aqueous composition comprising about 0.05% ± 0.005% tiloxapol; Wherein the pH of the composition is adjusted using NaOH or HCl to be about 6.2 to about 6.8, and the osmolarity of the composition is adjusted using NaCl to be about 250 to about 350 mOsm / kg. In some embodiments, the amount of NaCl is about 0.50% ± 0.05%.

In some embodiments, including but not limited to the sterile composition, the composition consists of only the ingredients listed, and any additional active ingredients, excipients (eg, viscosity constituents, buffers, chelating agents, stabilizers, preservatives) , Surfactants, and isotonic agents), carriers or diluents. In some embodiments, the amount of any one or more of the listed components is provided in an amount that is ± 5%, and / or ± 1% of the listed amount.

In some embodiments, the compositions disclosed herein are prepared as a solution, gel or ointment. Gels or ointments provide advantages or other advantages in providing a composition that is in contact with the eye for a longer time than the solution. Thus, in one embodiment, the gel or ointment may be applied when the composition is applied to the composition, when the subject is sleeping, or when the subject's eyes have been extended (eg, 1, 2, 3, 4, 5). Useful when wound for more than this time). Gels or ointments may be used at other times based on user preferences.

Nonlimiting exemplary compositions (which may be used in the methods and kits disclosed herein) include the following compositions in Tables 1.1, 1.2, 1.3, and 1.4.

TABLE 1.1

TABLE 1.2

Table 1.3

Table 1.4

Embodiments of the compositions of Tables 1.1-1.4 also provide a range of ± 1% of the disclosed amount, ± 2% of the disclosed amount, ± 3% of the disclosed amount, ± 4% of the disclosed amount, or disclosed amount. A composition having an amount of the disclosed component in a range of ± 5%. In some embodiments, the compositions of Tables 1.1-1.4 have at least 1 or 2 weeks, 1, 2, 3, 4 or 5 at −20 ± 5 ° C., 5 ± 3 ° C. or 25 ± 2 ° C. and 25 ± 5% relative humidity. After storage of the composition for months, the composition retains at least about 99.0%, 99.9%, 99.95%, or 99.99% of the racopeptide polypeptide of SEQ ID NO: 1 in its initial undigested form. In some embodiments, the compositions of Tables 1.1-1.4 are at least about 80% or 90% in their initial undigested form in the composition after storage of the composition for at least 12 months at −20 ± 5 ° C. or 5 ± 3 ° C. Retains the racopeptide polypeptide of SEQ ID NO: 1. In some embodiments, the compositions of Tables 1.1-1.4 contain about 0.2-0.8%, or about 0.5% NaCl.

Other therapeutic ingredients

In some embodiments, the composition comprises one or more additional therapeutic agents in addition to the polypeptides disclosed herein. These therapeutic agents may include substances known to those skilled in the art for the treatment of dry eye syndromes and related syndromes and diseases including Sjogren's syndrome. The additional therapeutic ingredient may treat the disease, syndrome or disease, or alleviate the symptoms associated with the disease, syndrome or disease. An incomplete list of additional therapeutic agents includes the following: choline-based (e.g., pilocarpine, cevimelin), cyclosporin, Lipitegrast, dexamethasone (or other cortico-steroids such as prednisolone), chondroitin Hyaluronic acid with and without sulfate (and derivatives thereof), Cyclokat, SI-614, skQ1, cis-UCA, cycloASol, RGN-259, diquafosol, anakinra, tofacitinib, EBI- 005, EGP-437, KP-121, MIM-D3, OTX-DP, Revamipid (OPC-12759), and RU-101. In some embodiments, the additional therapeutic agent is Xiidra (Lipitegrast, SAR-1118). In some embodiments, one or more additional therapeutic agents are provided as salts of the polypeptide. Carboxymethyl cellulose, polyvinyl alcohol, hydroxypropyl methylcellulose (also known as HPMC or hypromellose), hydroxypropyl cellulose, ethylene glycol polymer, and hyaluronic acid (also known as hyaluronan, HA), and tears Ointments such as white petrolatum, mineral oil, and other lubricants and artificial tears containing one or more of similar lubricants may be included in the composition. These additional therapeutic agents may be included in known therapeutic amounts, or in amounts below the therapeutic amount.

Containers and kits

In some embodiments, the composition is provided in a kit comprising one or more multi-use containers. In some embodiments, the multi-use container includes a protective cap and a liquid reservoir, where the cap is connected to the bottle via a flexible connector. The blocking plug is arranged in the middle of the top surface of the protective cap. A conical, or other suitable shaped liquid outlet is arranged in the middle of the bottle cover and tightly connected to the blocking plug of the protective cap. Thus, the sterile composition can be placed in a container for multiple use.

In some embodiments, the amount of the composition in the container is in the range 0.1-0.5, 0.5-1.0, 1-2, 2-5, 5-10, 10-20, 20-30, or 30-60 mL or between , Or an approximation thereof. The container may be a bottle, tube, vials or other suitable container. Multi-use containers may be accompanied by instructions for use during a 12 hour, 24 hour, 2-7 day cycle, 1 month cycle or until the stated expiration date. Disposable containers may be suitable for use in one eye or two eyes during a single application cycle.

In some embodiments, the composition is provided in a kit comprising a disposable container. In some embodiments, the composition is provided in a kit comprising a plurality of disposable containers. In some embodiments, the disposable container includes a vessel for holding a liquid, a removable sealing top for sealing the liquid container, and optionally a neck portion interconnecting the container and the sealing top. Kits comprising a plurality of disposable containers with instructions for use are provided in many embodiments.

In some embodiments, the container comprises a pharmaceutically inert substance. In some embodiments, the container is glass, polyvinyl chloride, polypropylene, polyethylene terephthalate, polyethylene terephthalate, polyethylene terephthalate 프 G, high density polyethylene, low density polyethylene, polybutylene terephthalate, polyurethane, polyethylene vinyl acetate, silicone, Acrylonitrile butadiene styrene, polytetrafluoroethylene, polycarbonate, polystyrene, polymethylmethacrylate, polysulfone, polyvinylidene chloride, or combinations thereof.

In some embodiments, the container comprises polyvinyl chloride, polypropylene, low density polyethylene, polyurethane, polyethylene vinyl acetate, silicone, or a combination thereof.

In some embodiments, the amount of the composition in the container is 0.02 mL; 0.05 mL to 1 mL; 0.1 mL to 0.95 mL; 0.15 mL to 0.8 mL; 0.2 mL to 0.85 mL; 0.25 mL to 0.8 mL; 0.3 mL to 0.75 mL; 0.35 mL to 0.7 mL; 0.4 mL to 0.65 mL; 0.45 mL to 0.6 mL; 0.5 mL to 0.55 mL; Or any amount in between or an approximation thereof.

In some embodiments, the amount of the composition in the container is 0.02 mL; 0.025 mL; 0.030 mL; 0.035 mL; 0.040 mL; 0.045 mL; 0.050 mL; 0.055 mL; 0.060 mL; 0.065 mL; 0.070 mL; 0.075 mL; 0.1 mL; 0.15 mL; 0.2 mL; 0.25 mL; 0.3 mL; 0.35 mL; 0.4 mL; 0.45 mL; 0.5 mL; 0.55 mL; 0.6 mL; 0.65 mL; 0.7 mL; 0.75 mL; 0.8 mL; 0.85 mL; 0.9 mL; 0.95 mL; Or an amount within the range defined by 1 mL of the composition, or any two, or an approximation thereof.

Ophthalmology and other administration

In some embodiments, the composition is administered topically to the eye. In some embodiments, the composition is administered for its treatment to a person suffering from dry eye, or dry eye (or other symptoms such as dry mouth) associated with Sjogren's syndrome. In some embodiments, it is administered as an oral rinse, tap, patch, spray or lozenge for the mouth. The compositions described herein may be provided as liquids (solutions, gels, ointments, etc.) or in other suitable forms such as powders or patches, tabs and the like. In some embodiments, the compositions described herein are used to achieve one or more of the following: to restore basal tears, saliva secretion, general mucosal and ocular surface wetting; Promotes autophagy to restore ocular surface and mucosal homeostasis and to eradicate pressure, stress or degenerative diseases rapidly but temporarily throughout the eye and in other organs; Reduces inflammation, promotes wound healing (such as corneal refraction surgery or oral wound healing), stabilizes tear lipid layer, and inhibits bacterial infection.

In some embodiments, topical administration in the eye comprises administering one or more droplets of the composition at the surface of the eye. For example, in one embodiment, the user is instructed to apply to the eye surface rather than the contact lens). In other embodiments, the droplets (or other applications) are suitable for administration when wearing contact lenses. In some embodiments, the composition is administered from a container in a single dose delivered as a single drop in each eye. In some embodiments, the droplets are about 0.020 mL to about 0.050 mL, or any volume between them. In some embodiments, the droplets are about 0.035 mL.

In some embodiments, administration of the composition to the eye improves one or more patients for whom symptoms or clinical signs of dry eye syndrome or Sjogren's syndrome have been reported. Improvement in dry eye symptoms or signs can be assessed by one or more of the following:

플루오레세인 각막 염색(FCS)(5개의 영역에 대한 영역에 의한 0 내지 3 척도, 총 0-15 척도, (미국 국립 안연구소(NEI/Industry Workshop) 척도를 사용함)

Fluorescein corneal staining (FCS) (0-3 scale by region for 5 regions, 0-15 scale total, using US National Institute of Ophthalmology (NEI / Industry Workshop) scale)

리사민 그린 결막 염색(LGCS)(영역에 의한 0 내지 3 척도, 총 0-18 척도, 미국 국립 안연구소(NEI/Industry Workshop) 척도를 사용함)

Lysamine Green Conjunctival Staining (LGCS) (0-3 scale by region, 0-18 scale total, using US National Eye Institute (NEI / Industry Workshop) scale)

마취된 쉬르머 시험(5분 내의 습윤의 mm)

Anesthesia Schirmer test (mm of wetting in 5 minutes)

눈물막 파괴 시간(초 단위의 수)

Tear film break time (number of seconds)

시각 통증 척도에 대해 환자에 의해 기록되고, 기준선으로부터 평균 변화로서 표로 작성된 안구 건조도

Eye dryness, recorded by the patient on the visual pain scale and tabulated as mean change from baseline

안구 건조-관련된 안구 증상 설문지(SANDE: 안구 건조증 증상의 빈도 및 중증 정도), (문헌[Schaumberg D, et al. Development and Validation of a Short Global Dry Eye Symptom Index. The Ocular Surface. January 2007, Vol 5; 1; 50-57], 그 전문이 본원에 참조로 포함됨).

Dry eye-related ocular symptom questionnaire (SANDE: frequency and severity of dry eye symptoms), (Schaumberg D, et al. Development and Validation of a Short Global Dry Eye Symptom Index.The Ocular Surface. January 2007, Vol 5 1; 50-57, which is incorporated herein by reference in its entirety.

In some embodiments, the composition comprises about 0.001% to about 0.05% Lacripepe ^™ (SEQ ID NO. 1) or other peptides identified herein; About 0.001% to about 0.015% citric anhydride; About 0.02% to about 0.40% sodium citrate dihydrate; About 0.0005% to about 0.005% disodium EDTA; A sterile aqueous composition comprising, consisting of, or consisting essentially of about 0.005% to about 0.15% tiloxapol, and about 0.005% to about 0.1% methylparaben; Wherein the pH of the composition is adjusted using NaOH or HCl to be about 6.2 pH to about 6.8 pH, and the osmolarity of the composition is adjusted using NaCl to be about 250 to about 350 mOsm / kg. In some embodiments, the amount of NaCl is about 0.1% to about 1%. In one embodiment, the composition does not comprise methylparabens. In one embodiment, the composition consists only of the ingredients listed and any additional active ingredients, excipients (eg, viscosity constituents, buffers, chelating agents, stabilizers, preservatives, surfactants, and isotonic agents) Contains no carriers or diluents.

In some embodiments, the composition comprises about 0.001% to about 0.05% Lacripepe ^™ (SEQ ID NO: 1) or other peptides identified herein; About 0.001% to about 0.015% citric anhydride; About 0.02% to about 0.40% sodium citrate dihydrate; About 0.0005% to about 0.005% disodium EDTA; And from about 0.005% to about 0.15% of tiloxapol, or a sterile aqueous composition consisting essentially of; Wherein the pH of the composition is adjusted using NaOH or HCl to be about 6.2 pH to about 6.8 pH, and the osmolarity of the composition is adjusted using NaCl using about 250 to about 350 mOsm / kg. In some embodiments, the amount of NaCl is about 0.1% to about 1%. In one embodiment, the composition consists only of the ingredients listed and any additional active ingredients, excipients (eg, viscosity constituents, buffers, chelating agents, stabilizers, preservatives, surfactants, and isotonic agents) Contains no carriers or diluents.

In some embodiments, the composition comprises about 0.01% ± 0.001% Lacripeppe ^TM (SEQ ID NO: 1) or another peptide identified herein; About 0.0098% ± 0.001% citric anhydride; About 0.279% ± 0.028% sodium citrate dihydrate; About 0.001% ± 0.0001% of disodium EDTA; A sterile aqueous composition comprising about 0.05% ± 0.005% of tiloxapol; Wherein the pH of the composition is adjusted using NaOH or HCl to be about 6.2 to about 6.8, and the osmolarity of the composition is adjusted using NaCl to be about 250 to about 350 mOsm / kg. In some embodiments, the amount of NaCl is about 0.50% ± 0.05%.

In some embodiments, the composition comprises about 0.005% ± 0.0005% of Lacripep ^TM (SEQ ID NO. 1) or other peptides identified herein; About 0.0098% ± 0.001% citric anhydride; About 0.279% ± 0.028% sodium citrate dihydrate; About 0.001% ± 0.0001% of disodium EDTA; A sterile aqueous composition comprising about 0.05% ± 0.005% of tiloxapol; Wherein the pH of the composition is adjusted using NaOH or HCl to be about 6.2 to about 6.8, and the osmolarity of the composition is adjusted using NaCl using about 250 to about 350 mOsm / kg. In some embodiments, the amount of NaCl is about 0.50% ± 0.05%.

In some embodiments, the composition comprises about 0.001% ± 0.0001% Lacripepe ^TM (SEQ ID NO: 1) or other peptides identified herein; About 0.0098% ± 0.001% citric anhydride; About 0.279% ± 0.028% sodium citrate dihydrate; About 0.001% ± 0.0001% of disodium EDTA; A sterile aqueous composition comprising about 0.05% ± 0.005% of tiloxapol; Wherein the pH of the composition is adjusted using NaOH or HCl to be about 6.2 to about 6.8, and the osmolarity of the composition is adjusted using NaCl to be about 250 to about 350 mOsm / kg. In some embodiments, the amount of NaCl is about 0.50% ± 0.05%.

Some embodiments include a method of treating dry eye and / or primary Sjogren's syndrome comprising administering a composition disclosed herein to the eye of a subject having dry eye and / or primary Sjogren's syndrome. In one embodiment, the compositions described herein are used to treat Sjogren's syndrome. In some embodiments, the compositions described herein are used to treat a subject having one or more of the following criteria:

I. Eye Symptoms

o Dry eye symptoms for at least 3 months

o foreign body sensation

o Use of artificial tears more than 3 times / day

II. Oral symptoms

o Symptoms of dry mouth for at least 3 months

o recurrent or persistently swollen salivary glands

o The need for a liquid to swallow dry food

III. Eyeball signs

o abnormal anesthetic Schirmer test, (no anesthesia; ≤5mm / 5 min)

Positive Biological Pigment Staining of Eye Surface

IV. Histopathology

o Lip biopsy showing focal lymphocytic salivary glanditis (1 per local score ≥4 mm2)

V. Oral Indications

o Unstimulated whole saliva flow (≤ 1.5 mL in 15 minutes)

o Abnormal parotid sialography

Abnormal saliva scintillation

VI. Autoantibodies

o anti-SSA (Ro) (anti-Shogren- Syndrome-related Antigen A) or anti-SSB (La) (anti-Shogren- Syndrome-related Antigen B), or both.

In one embodiment, the compositions described herein are used to treat a subject having at least one criterion from each of the six categories above. In some embodiments, the polypeptide or pharmaceutically acceptable salt thereof in the composition is Lacripep ^TM (Ac-Lys-Gln-Phe-Ile-Glu-Asn-Gly-Ser) in an amount of 0.005%, or 0.01%. Has a sequence consisting of -Glu-Phe-Ala-Gln-Lys-Leu-Leu-Lys-Lys-Phe-Ser-NH ₂ , where "Ac" represents an acetyl group and the C-terminus is amidated (SEQ ID NO: 1)). In some embodiments, the ophthalmic solution is citric acid (about 0.0098% anhydrous), sodium citrate (about 0.279% sodium citrate dihydrate), EDTA disodium (about 0.001%), NaCl (up to about 300 mOsm / kg), til USPs other than oxapol (about 0.05%), tiloxapol (about 0.05%), NaOH (up to about 6.5 pH), purified water, polypeptides, such as Lacripep ^™ . To assess efficacy, some embodiments use a placebo comprising a vehicle ophthalmic solution free of polypeptides. In some embodiments, one drop of the composition is administered to the eye of the subject up to three times a day. In some embodiments, the administering has a FCS total score in the eye of the subject at least two weeks after treatment, or at least four weeks after treatment, or at least six weeks after the start of four weeks of treatment compared to baseline measurements prior to initiating treatment (US National Industry Institute 0-15 scale). In some embodiments, administration improves one or more of the following:

Dry eye after at least 2 weeks of treatment or after at least 4 weeks of treatment, compared to the criteria for the visual pain scale;

SANDE (collective score SANDE-1) after at least two weeks of treatment, compared to baseline measurements prior to initiation of treatment;

An average score for SANDE (gross score SANDE-1) after at least two weeks of treatment, compared to baseline measurements prior to initiation of treatment;

Individual symptom evaluation (immediate) after at least two weeks of treatment compared to baseline measurements prior to initiation of treatment;

Mean score for individual symptom evaluation (reflective) after at least 2 weeks of treatment compared to baseline measurements prior to initiation of treatment;

LGCS in the subject's eye after at least two weeks of treatment, compared to baseline measurements prior to initiation of treatment;

Anesthesia Schirmer test in the eye of the subject after at least 2 weeks of treatment, compared to baseline measurements prior to initiation of treatment;

TFBUT in the eye of the subject after at least two weeks of treatment compared to baseline measurements prior to initiation of treatment;

FCS in the eye of the subject after at least two weeks of treatment, compared to baseline measurements prior to initiation of treatment;

SANDE at 1 week after at least 2 weeks of treatment, or after at least 4 weeks of treatment, or 4 weeks of treatment compared to baseline measurements prior to initiation of treatment (overall score for SANDE 1);

Individual symptoms (immediate) at week 1 after at least 2 weeks of treatment, or after at least 4 weeks of treatment, or 4 weeks of treatment, compared to baseline measurements before initiation of treatment;

An average score for (Gross Score SANDE-2) at Week 1 after at least 2 weeks of treatment, after at least 4 weeks of treatment, or after 4 weeks of treatment, compared to baseline measurements before initiation of treatment;

An average score for individual symptom evaluation (reflective) at 1 week after at least 2 weeks of treatment, or after at least 4 weeks of treatment, or 4 weeks of treatment, compared to baseline measurements before initiation of treatment;

FCS and SANDE 1 and individual symptom assessments (immediately) after at least two weeks of treatment, or after at least four weeks of treatment, or four weeks of treatment, compared to baseline measurements before initiation of treatment;

LGCS after at least 2 weeks of treatment or after at least 4 weeks of treatment compared to baseline measurements prior to initiation of treatment;

Anesthesia Schirmer test results after at least 2 weeks of treatment or after at least 4 weeks of treatment compared to baseline measurements prior to initiation of treatment;

TFBUT at 1 week after at least 2 weeks of treatment, or after at least 4 weeks of treatment, or 4 weeks of treatment, compared to baseline measurements prior to initiation of treatment.

In some embodiments, the comparison comprises instead or additionally a comparison to the vehicle control.

In one embodiment, any one or more of the following drugs / therapys are not co-administered with a composition described herein, and in one embodiment, any one or more of the following drugs / therapys are co-administered with a composition described herein :

Ophthalmic drugs (optional topical eye drops), including prescription and over-the-counter [OTC] formulations

contact lens

Any ocular surface or eyelid surgical procedure within 365 days prior to treatment or intraocular surgery within 90 days prior to treatment

Amiodarone.

Topical ocular antihistamines

Ocular, inhaled or intranasal corticosteroids

Topical or Oral Mast Cell Stabilizers

Oral antihistamines

Topical or nasal vasoconstrictors

Topical ocular NSAID

Topical eye antibiotics

Within 60 days and / or the course of treatment: topical cyclosporine, topical lipiditegra

Within 90 days prior to treatment and / or the course: cauterization of the tear point or (insertion or removal) alteration of the tear point plug (s) or nose tear surgery.

Chronic oral anti-viral drug for ocular herpes disease.

Example

Non-limiting examples of some of the embodiments described herein are as follows.

Example 1 Peptide Composition Stability

Many Lacripep ^TM (SEQ ID NO: 1) ophthalmic formulations are available at 1, 2, 1, 2, 3, 4 at -20 ° C, 5 ° C, 25 ° C / 25% relative humidity or 25 ° C / 60% relative humidity. Stability was tested at months, and at 12 months. These formulations are shown in Table 1.5 and stability data are shown in Table 2 (as degradation products represented as w / w percentage of initial amount of Lacripepe ^™ ) and Table 3 (12 month data). Under all conditions tested, each formulation remained a clear colorless solution and the packaging did not leak or discolor.

Table 1.5 Lacripep ^TM Formulations for Stability Studies

TABLE 2 Lacripep ^TM Formulation Stability, pH and Degradation Product% w / w

TABLE 3 Lacripep ^TM formulation stability at 12 months, 5 ° C.

Example 2 Comparative Peptide Stability

Lacripept ^™ (SEQ ID NO: 1) stability was assessed in PBS at pH 4.5 and 7.0 (FIG. 1) and citrate buffer at pH 6.0 and 6.5 (FIG. 2). The initial concentration of Lacripep ^™ was 0.001% and each test was run at 60 ° C. Stability was assessed using MALDI TOF mass spectrometry at the start of the experiment (week 0, top panel FIGS. 1 and 2) and after 2 weeks (2 weeks, bottom panel FIGS. 1 and 2). After two weeks in PBS to pH 4.5 and 7.0, significant degradation is indicated by the appearance of the new lower m / e peak, for example, at 993.9 (m / e) (small arrow, lower panel in FIG. 1). Observed at the ^TM peak (large arrow). On the other hand, after two weeks in citrate buffer to pH 6.0 and 6.5, the intensity of Lacripep ^™ peak (large arrow), or the change in appearance of any new lower m / e peak (FIG. 2, lower panel) does not exist. This demonstrates an unexpected improvement in peptide stability in citrate buffer.

Example 3-Composition Preparation Process

Table 4 summarizes the processes described below.

Sterile purified water (part I) and methylparaben are added to an appropriately sized production liquid container. Using propeller mixing, the mixture is heated to 65 ° C. ± 5 ° C. until methylparaben is dissolved to a clear solution and then removed from heat. If necessary to obtain a clear solution, the mixture can be heated up to 80 ° C ± 2 ° C.

Using further continuous propeller mixing, citric acid, sodium citrate, and EDTA disodium are added. All three components are dissolved and a clear solution is obtained and mixed until the temperature of the solution is below 22 ° C ± 2 ° C.

With further continuous propeller mixing, Tiloxapol and Lacripep ^™ (SEQ ID NO: 1) are added and mixed until a clear solution is obtained.

If necessary, adjust the pH of the bulk solution to 6.5 ± 0.3 with 10% NaOH (aq) or 10% HCl (aq). Mix until the solution is homogeneous.

If necessary, adjust the osmolarity of the solution at 300 ± 20 mOsm / kg with 25% NaCl (aq).

Purified water (part II) is added in a batch sufficient to batch to 100%. Mix with a propeller until the solution is homogeneous.

TABLE 4 Process (A)

Example 4-Composition Preparation Process-Preservative-Free Composition

Table 5 summarizes the processes described below.

Sterile purified water (part I) is added to an appropriately sized production liquid container. Continuous propeller mixing is used to add citric acid, sodium citrate, and EDTA disodium. All three components are dissolved and a clear solution is obtained and mixed until the temperature of the solution is below 22 ° C ± 2 ° C.

Using further continuous propeller mixing, Tyloxapol and Lacripep ^™ (SEQ ID NO: 1) are added and mixed until a clear solution is obtained.

If necessary, adjust the pH of the bulk solution to 6.5 ± 0.3 with 10% NaOH (aq) or 10% HCl (aq). Mix until the solution is homogeneous.

If necessary, adjust the osmolarity of the solution at 300 ± 20 mOsm / kg with 25% NaCl (aq).

Table 5-Process (B)

Example 5 Composition Preparation Process

Table 6 summarizes the processes described below.

Sterile purified water (part I) is added to an appropriately sized production liquid container. Continuous propeller mixing is used to add citric acid, sodium citrate, and EDTA disodium. All three components are dissolved and a clear solution is obtained and mixed until the temperature of the solution is below 22 ° C ± 2 ° C.

With further continuous propeller mixing, Tiloxapol and Lacripep ^™ (SEQ ID NO: 1) are added and mixed until a clear solution is obtained.

If necessary, adjust the pH of the bulk solution to 6.5 ± 0.3 with 10% NaOH (aq) or 10% HCl (aq). Mix until the solution is homogeneous.

If necessary, adjust the osmolarity of the solution at 300 ± 20 mOsm / kg with 25% NaCl (aq).

Table 6-Process (C)

For example, the composition may comprise less than 0.05% of an active ingredient such as a polypeptide (eg, 0.001-0.02%, 0.001-0.05%), or a pharmaceutically acceptable salt thereof; And one or more of the following: less than 0.6% buffer (eg, 0.001-.3%, 0.001-0.6%); (ii) less than 0.01% disodium EDTA (eg, 0%, 0.001-.005%, 0.001-0.01%); And (iii) less than 0.1% of tiloxapol (eg, 0%, 0.001-0.05%, 0.001-0.1%), and optionally other ingredients.

In addition, while described above in some detailed description by way of illustration and example for purposes of clarity and understanding, those skilled in the art will understand that many and various modifications may be made without departing from the spirit of the disclosure. . Accordingly, the forms disclosed herein are illustrative only and are not intended to limit the scope of the present disclosure, but rather to include all modifications and alternatives accompanying the actual scope and spirit of the embodiments of the invention (s). It must be understood.

Unless expressly stated to the contrary, the terms and phrases used herein, particularly the appended claims, and variations thereof, are to be interpreted in an open fashion as opposed to a restrictive one. As an example of the above, the term 'comprising' should be read to mean 'including without limitation', 'including without limitation' and the like.

The singular expression "a" or "an" does not exclude a plurality. The use of "medicine" before a number includes the number itself. For example, "about 5" provides an expression base for "5."

<110> Laurie, Gordon W.          Odrich, Marc G.          Carpenter, Michelle          Gadek, Thomas R.          Laskar, Paul A. <120> STABLE PEPTIDE COMPOSITION <130> TEAR.003WO <150> 62 / 461,467 <151> 2017-02-21 <150> 62 / 530,565 <151> 2017-07-10 <160> 9 FastSEQ for Windows Version 4.0 <210> 1 <211> 19 <212> PRT <213> Homo sapiens <220> <221> MOD_RES <222> (1) <223> ACETYLATION <220> <221> MOD_RES <222> (19) <223> AMIDATION <400> 1 Lys Gln Phe Ile Glu Asn Gly Ser Glu Phe Ala Gln Lys Leu Leu Lys   1 5 10 15 Lys Phe Ser             <210> 2 <211> 25 <212> PRT <213> Homo sapiens <220> <221> MOD_RES <222> (1) <223> ACETYLATION <220> <221> MOD_RES <222> (25) <223> AMIDATION <400> 2 Lys Gln Phe Ile Glu Asn Gly Ser Glu Phe Ala Gln Lys Leu Leu Lys   1 5 10 15 Lys Phe Ser Leu Leu Lys Pro Trp Ala              20 25 <210> 3 <211> 138 <212> PRT <213> Homo sapiens <400> 3 Met Lys Phe Thr Thr Leu Leu Phe Leu Ala Ala Val Ala Gly Ala Leu   1 5 10 15 Val Tyr Ala Glu Asp Ala Ser Ser Asp Ser Thr Gly Ala Asp Pro Ala              20 25 30 Gln Glu Ala Gly Thr Ser Lys Pro Asn Glu Glu Ile Ser Gly Pro Ala          35 40 45 Glu Pro Ala Ser Pro Pro Glu Thr Thr Thr Thr Ala Gln Glu Thr Ser      50 55 60 Ala Ala Ala Val Gln Gly Thr Ala Lys Val Thr Ser Ser Arg Gln Glu  65 70 75 80 Leu Asn Pro Leu Lys Ser Ile Val Glu Lys Ser Ile Leu Leu Thr Glu                  85 90 95 Gln Ala Leu Ala Lys Ala Gly Lys Gly Met His Gly Gly Val Pro Gly             100 105 110 Gly Lys Gln Phe Ile Glu Asn Gly Ser Glu Phe Ala Gln Lys Leu Leu         115 120 125 Lys Lys Phe Ser Leu Leu Lys Pro Trp Ala     130 135 <210> 4 <211> 119 <212> PRT <213> Homo sapiens <400> 4 Glu Asp Ala Ser Ser Asp Ser Thr Gly Ala Asp Pro Ala Gln Glu Ala   1 5 10 15 Gly Thr Ser Lys Pro Asn Glu Glu Ile Ser Gly Pro Ala Glu Pro Ala              20 25 30 Ser Pro Pro Glu Thr Thr Thr Thr Ala Gln Glu Thr Ser Ala Ala Ala          35 40 45 Val Gln Gly Thr Ala Lys Val Thr Ser Ser Arg Gln Glu Leu Asn Pro      50 55 60 Leu Lys Ser Ile Val Glu Lys Ser Ile Leu Leu Thr Glu Gln Ala Leu  65 70 75 80 Ala Lys Ala Gly Lys Gly Met His Gly Gly Val Pro Gly Gly Lys Gln                  85 90 95 Phe Ile Glu Asn Gly Ser Glu Phe Ala Gln Lys Leu Leu Lys Lys Phe             100 105 110 Ser Leu Leu Lys Pro Trp Ala         115 <210> 5 <211> 114 <212> PRT <213> Homo sapiens <400> 5 Asp Ser Thr Gly Ala Asp Pro Ala Gln Glu Ala Gly Thr Ser Lys Pro   1 5 10 15 Asn Glu Glu Ile Ser Gly Pro Ala Glu Pro Ala Ser Pro Pro Glu Thr              20 25 30 Thr Thr Thr Ala Gln Glu Thr Ser Ala Ala Ala Val Gln Gly Thr Ala          35 40 45 Lys Val Thr Ser Ser Arg Gln Glu Leu Asn Pro Leu Lys Ser Ile Val      50 55 60 Glu Lys Ser Ile Leu Leu Thr Glu Gln Ala Leu Ala Lys Ala Gly Lys  65 70 75 80 Gly Met His Gly Gly Val Pro Gly Gly Lys Gln Phe Ile Glu Asn Gly                  85 90 95 Ser Glu Phe Ala Gln Lys Leu Leu Lys Lys Phe Ser Leu Leu Lys Pro             100 105 110 Trp Ala         <210> 6 <211> 114 <212> PRT <213> Homo sapiens <400> 6 Glu Asp Ala Ser Ser Asp Ser Thr Gly Ala Asp Pro Ala Gln Glu Ala   1 5 10 15 Gly Thr Ser Lys Pro Asn Glu Glu Ile Ser Gly Pro Ala Glu Pro Ala              20 25 30 Ser Pro Pro Glu Thr Thr Thr Thr Ala Gln Glu Thr Ser Ala Ala Ala          35 40 45 Val Gln Gly Thr Ala Lys Val Thr Ser Ser Arg Gln Glu Leu Asn Pro      50 55 60 Leu Lys Ser Ile Val Glu Lys Ser Ile Leu Leu Thr Glu Gln Ala Leu  65 70 75 80 Ala Lys Ala Gly Lys Gly Met His Gly Gly Val Pro Gly Gly Lys Gln                  85 90 95 Phe Ile Glu Asn Gly Ser Glu Phe Ala Gln Lys Leu Leu Lys Lys Phe             100 105 110 Ser leu         <210> 7 <211> 109 <212> PRT <213> Homo sapiens <400> 7 Glu Asp Ala Ser Ser Asp Ser Thr Gly Ala Asp Pro Ala Gln Glu Ala   1 5 10 15 Gly Thr Ser Lys Pro Asn Glu Glu Ile Ser Gly Pro Ala Glu Pro Ala              20 25 30 Ser Pro Pro Glu Thr Thr Thr Thr Ala Gln Glu Thr Ser Ala Ala Ala          35 40 45 Val Gln Gly Thr Ala Lys Val Thr Ser Ser Arg Gln Glu Leu Asn Pro      50 55 60 Leu Lys Ser Ile Val Glu Lys Ser Ile Leu Leu Thr Glu Gln Ala Leu  65 70 75 80 Ala Lys Ala Gly Lys Gly Met His Gly Gly Val Pro Gly Gly Lys Gln                  85 90 95 Phe Ile Glu Asn Gly Ser Glu Phe Ala Gln Lys Leu Leu             100 105 <210> 8 <211> 104 <212> PRT <213> Homo sapiens <400> 8 Glu Asp Ala Ser Ser Asp Ser Thr Gly Ala Asp Pro Ala Gln Glu Ala   1 5 10 15 Gly Thr Ser Lys Pro Asn Glu Glu Ile Ser Gly Pro Ala Glu Pro Ala              20 25 30 Ser Pro Pro Glu Thr Thr Thr Thr Ala Gln Glu Thr Ser Ala Ala Ala          35 40 45 Val Gln Gly Thr Ala Lys Val Thr Ser Ser Arg Gln Glu Leu Asn Pro      50 55 60 Leu Lys Ser Ile Val Glu Lys Ser Ile Leu Leu Thr Glu Gln Ala Leu  65 70 75 80 Ala Lys Ala Gly Lys Gly Met His Gly Gly Val Pro Gly Gly Lys Gln                  85 90 95 Phe Ile Glu Asn Gly Ser Glu Phe             100 <210> 9 <211> 14 <212> PRT <213> Homo sapiens <400> 9 Asn Gly Ser Glu Phe Ala Gln Lys Leu Leu Lys Lys Phe Ser   1 5 10

Claims (55)

As a liquid composition,
0.00001-0.1%, or 0.001-0.05% polypeptide, or a pharmaceutically acceptable salt thereof;
0.01-0.6% buffer;
Absent or 0.0005-0.01% disodium EDTA;
Absent or 0.01-0.1% tiloxapol,
And sodium chloride,
Wherein the pH of the composition is from 6.2 to about 6.8 and the osmolality of the composition is from about 250 to 350 mOsm / kg. The method of claim 1, wherein the polypeptide is 0.01% or 0.005%, or a pharmaceutically acceptable salt thereof;
The buffer is 0.25-0.31, or 0.2888%;
The disodium EDTA is 0.001%;
The tiloxapol is 0.05%,
The pH of the composition is from 6.2 to about 6.8, the osmolarity of the composition is from about 250 to 350 mOsm / kg,
The polypeptide is Lacripep having SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof. The composition of claim 1 or 2, wherein the buffer is citrate buffer. The composition of claim 3 wherein the citrate buffer comprises 0.0098% citric anhydride and 0.279% sodium citrate dihydrate. 5. The composition of claim 1, wherein the pH of the composition is about 6.5. The composition of claim 1, wherein the osmolarity of the composition is between 280 and 320 mOsm / kg. The composition according to any one of claims 1 to 6, wherein the osmolarity of the composition is 300 mOsm / kg. The composition of claim 1, wherein the amount of NaCl is 0.4% to 0.6%. The composition of claim 1, wherein the amount of NaCl is 0.5%. The composition of claim 1, wherein the composition further comprises 0.04% methylparaben. The composition of any one of the preceding claims, wherein the composition is sterile. A kit comprising a plurality of disposable containers, each container comprising a vessel for holding the composition of any one of claims 1-11. The kit of claim 12, wherein the container comprises about 0.05 mL to about 1 mL of the composition. The kit of claim 12 or 13, wherein the container comprises a removable sealing top for sealing the liquid container, and a neck portion interconnecting the liquid container and the sealing top part. 15. The kit of claim 14, wherein said removable sealing top is incapable of resealing said liquid container once removed. The container according to claim 12, wherein the container is polyvinyl chloride, polypropylene, polyethylene terephthalate, polyethylene terephthalate, polyethylene terephthalate 폴리에틸렌 G, high density polyethylene, low density polyethylene, polybutylene terephthalate, poly A kit comprising urethane, polyethylene vinyl acetate, silicone, acrylonitrile butadiene styrene, polytetrafluoroethylene, polycarbonate, polystyrene, polymethylmethacrylate, polysulfone, polyvinylidene chloride, or a combination thereof. A method of administration comprising topically applying one or more droplets of the composition of any one of claims 1 to 11 to the eye. 18. The method of claim 17, wherein the administration further comprises topically applying one drop of the composition to the eye from the disposable container of any one of claims 12-16. Use of the composition of any one of claims 1 to 11 for the treatment of dry eye. Use of the composition of claim 1 for the treatment of one or more symptoms of Sjogren's syndrome. As a topical composition,
0.005-0.05% polypeptide, and one or more of the following:
0.1-0.6% buffer;
0.0005-0.01% disodium EDTA;
0.01-0.1% tiloxapol,
And sodium chloride
Including,
Wherein the composition is a solution, gel or ointment. The composition of claim 21, wherein the polypeptide is provided in an amount of 0.001 to 0.01%. 23. The composition of claim 21 or 22, wherein the polypeptide is a tear glycoprotein or fragment thereof. The composition of any of claims 21-23, wherein the polypeptide is any one of SEQ ID NOs: 1-9. 25. The composition of any one of claims 21 to 24, wherein said polypeptide is lacripepe. 26. The composition of any one of claims 21-25 for use in treating one or more symptoms of dry eye syndrome or Sjogren's syndrome. 27. A method of treating dry eye and / or primary Sjogren's syndrome comprising administering to the eye of a subject having dry eye and / or primary Sjogren's syndrome the composition of any one of claims 1 to 26
The polypeptide or a pharmaceutically acceptable salt thereof is in an amount of 0.005%, or 0.01%,
The polypeptide is a sequence consisting of Ac-Lys-Gln-Phe-Ile-Glu-Asn-Gly-Ser-Glu-Phe-Ala-Gln-Lys-Leu-Leu-Lys-Lys-Phe-Ser-NH ₂ , Wherein "Ac" represents an acetyl group, and has a C-terminal amidated sequence (SEQ ID NO: 1),
One droplet is administered to the eye of the subject up to three times per day. The subject's eye FCS according to claim 27, wherein said administering is in the subject's eye at least two weeks after treatment, or at least four weeks after treatment, or at least six weeks after the start of four weeks of treatment compared to baseline measurements prior to initiating treatment. How to improve the total score (US-15 Industry Scale 0-15). The method of claim 27 or 28, wherein said administering ameliorates one or more of the following:
Dry eye after at least 2 weeks of treatment or after at least 4 weeks of treatment, compared to the criteria for the visual pain scale;
SANDE (collective score SANDE-1) after at least two weeks of treatment, compared to baseline measurements prior to initiation of treatment;
An average score for SANDE (gross score SANDE-1) after at least two weeks of treatment, compared to baseline measurements prior to initiation of treatment;
Individual symptom evaluation (immediate) after at least two weeks of treatment compared to baseline measurements prior to initiation of treatment;
Mean score for individual symptom evaluation (Reflective) after at least 2 weeks of treatment, compared to baseline measurements prior to initiation of treatment;
LGCS in the subject's eye after at least two weeks of treatment, compared to baseline measurements prior to initiation of treatment;
Anesthesia Schirmer test in the eye of the subject after at least two weeks of treatment, compared to baseline measurements before initiation of treatment;
TFBUT in the eye of the subject after at least two weeks of treatment compared to baseline measurements prior to initiation of treatment;
FCS in the eye of the subject after at least two weeks of treatment, compared to baseline measurements prior to initiation of treatment;
SANDE at 1 week after at least 2 weeks of treatment, or after at least 4 weeks of treatment, or 4 weeks of treatment compared to baseline measurements prior to initiation of treatment (overall score for SANDE 1);
Individual symptoms (immediate) at week 1 after at least 2 weeks of treatment, or after at least 4 weeks of treatment, or 4 weeks of treatment, compared to baseline measurements before initiation of treatment;
An average score for (Gross Score SANDE-2) at Week 1 after at least 2 weeks of treatment, after at least 4 weeks of treatment, or after 4 weeks of treatment, compared to baseline measurements before initiation of treatment;
An average score for individual symptom evaluation (reflective) at 1 week after at least 2 weeks of treatment, or after at least 4 weeks of treatment, or 4 weeks of treatment, compared to baseline measurements before initiation of treatment;
FCS and SANDE 1 and individual symptom assessments (immediately) after at least two weeks of treatment, or after at least four weeks of treatment, or four weeks of treatment, compared to baseline measurements before initiation of treatment;
LGCS after at least 2 weeks of treatment or after at least 4 weeks of treatment compared to baseline measurements prior to initiation of treatment;
Anesthesia Schirmer test results after at least 2 weeks of treatment or after at least 4 weeks of treatment compared to baseline measurements prior to initiation of treatment;
TFBUT at 1 week after at least 2 weeks of treatment, or after at least 4 weeks of treatment, or 4 weeks of treatment, compared to baseline measurements prior to initiation of treatment. The method of claim 27, wherein administration of the composition to a group of subjects does not result in a significantly higher rate of side effects compared to the rate of side effects for administration of a placebo to a similar group of subjects. Way. The method of claim 27, wherein administration of the composition to a group of subjects does not result in a statistically higher rate of side effects compared to the rate of side effects for administration of a placebo to a similar group of subjects. Way. 30. The method of any one of claims 27-29, wherein administration of the composition to a group of subjects results in a statistically higher proportion of severe side effects compared to the rate of serious side effects for administration of a placebo to a similar group of subjects. How not to cause. 33. The method of any one of claims 1-32, wherein the concentration of said polypeptide or pharmaceutically acceptable salt thereof is about 0.005%. 34. The method of any one of claims 1-33, wherein the concentration of the polypeptide or a pharmaceutically acceptable salt thereof is about 0.01%. 35. The method of any one of claims 1-34, wherein the subject meets all of the following criteria:
Age 18 years or older;
Prior history or current diagnosis as documented of primary Sjogren's syndrome according to the US-European consensus group Sjogren's syndrome criteria with 4 of 6 total criteria or 3 of 4 signs;
If the subject receives systemic (oral) therapy for the treatment of Sjögren's syndrome, the subject must receive stable systemic treatment defined as the same treatment for the immediate 90 days;
Persons with a history of dry eye-related ocular symptoms, and self-recorded use of over the counter ocular humectants within the past 120 days; And
Meet all of the following criteria prior to the start of treatment:
a) Fluorescein corneal staining (FCS) total score ≧ 4 and <15 (where 0 = no staining) on the US National Eye Institute (NEI / Industry Workshop) scale;
b) score of symptom ≥40 using the SANDE questionnaire
c) anesthetized Schirmer test score of ≦ 5 mm wet / 5 min.
d) Lysamine Green Conjunctival Staining (LGCS) total score of ≧ 5 using the US National Eye Institute (NEI / Industry Workshop) scale, where 0 = no staining;
Here, the subject must meet all four criteria in at least one identical eye at the time of visit. 36. The method of any one of claims 1 to 35, wherein the subject does not meet one or more of the following criteria:
Any active infectious eye condition;
Having monocular, or worse corrected visual acuity (BCVA) as assessed by corrective lenses of +1.0 logMAR or, if necessary, by the Diabetic Retinopathy Early Treatment Study (ETDRS);
Ocular inflammatory conditions not associated with dry eye syndrome (eg, conjunctivitis, keratitis, anterior blepharitis, etc.);
Clinical evidence of scarring ocular surface diseases such as scarring ocular pseudophobic or Stephen Johnson syndrome;
The use of any topical eye drops (including topical cyclosporin) may not be stopped in the course of treatment with the composition;
Restasis® (topical ophthalmic cyclosporine) was used within 60 days prior to beginning treatment with the composition;
Xiidra® (topical ophthalmic lipidate) was used within 60 days prior to the start of treatment with the composition;
The subject's eye has a Fluorescein Corneal Stain (FCS) total score = 15 or a score = 3 on the US National Institute of Ophthalmology (NEI / Industry Workshop) scale of excellent areas or the subject's eye diffuse diffuse staining confluent staining), filaments, or FCS with obvious epithelial defects;
Subjects with or having an activity of herpetic keratitis within 365 days of initiation of treatment or receiving chronic oral antiviral agents for herpes disease;
Inability to stop and refrain from using contact lenses during the course of treatment;
Have a history of collagen vascular disease, autoimmune disease, or rheumatic disease (eg, lupus, rheumatoid arthritis, etc.) other than primary Sjogren's syndrome;
Have a current anterior membrane disorder or a history thereof;
Had corneal transplant or similar corneal surgery (DALK, DSEK, DMEK, etc.);
Used or expected use of amiodarone;
Dose or changes to the following doses are expected within 30 days prior to treatment start: tetracycline, omega 3 or omega 6;
Persons expecting a change in dose or within 60 days prior to the start of treatment and / or for the duration of treatment: anticholinergics, antidepressants, oral contraceptives, isotretinoin, oral systemic corticosteroids, oral systemic immunosuppressants,
Topical ocular antihistamines, ocular, inhaled or intranasal corticosteroids, topical or oral mast cell stabilizers, oral antihistamines, topical or nasal vasoconstrictors, topical ocular NSAIDs within 30 days prior to the start of treatment and / or for the duration of the study. Topical ocular antibiotics were used;
The subject's eye had a cauterization of the punctum or a change to the (insert or remove) tear point plug (s) within the past 90 days prior to the start of treatment;
In the eye of the subject had corneal refractive surgery (LASIK, PRK, RK);
History of any surgical procedure on the ocular surface or eyelid within 365 days prior to treatment start with a history of intraocular surgery within 90 days prior to start of treatment;
Pregnant or suspected of being pregnant;
Breastfeeding or intend to breastfeed; And
Participate in a device or investigational drug study or clinical trial within 30 days of starting treatment. The method of claim 1, wherein the polypeptide is Ac-Lys-Gln-Phe-Ile-Glu-Asn-Gly-Ser-Glu-Phe-Ala-Gln-Lys-Leu-Leu- A composition, kit or method having a sequence consisting of Lys-Lys-Phe-Ser-NH ₂ , wherein “Ac” represents an acetyl group and the C-terminus is amidated. 38. The composition, kit or method of any one of the preceding claims, wherein the amount of polypeptide or pharmaceutically acceptable salt thereof is 0.01% or 0.005%. The composition, kit, or any one of claims 1-38, wherein the comparison with the reference measurement prior to the start of treatment comprises instead or additionally a comparison of the treatment with the polypeptide relative to the vehicle control. Way. 40. The composition of claim 1, wherein the composition is
0.001-0.05% polypeptide, or a pharmaceutically acceptable salt thereof;
0.01-0.6% buffer;
0.0005-0.01% disodium EDTA;
0.01-0.1% tiloxapol,
And sodium chloride,
Wherein the pH of the composition is from 6.2 to about 6.8 and the osmolarity of the composition is from about 250 to 350 mOsm / kg. The method of claim 40, wherein the polypeptide is 0.01% or a pharmaceutically acceptable salt thereof;
The buffer is 0.2888%;
The disodium EDTA is 0.001%;
The tiloxapol is 0.05%,
The pH of the composition is from 6.2 to about 6.8, the osmolarity of the composition is from about 250 to 350 mOsm / kg,
The polypeptide is a composition, kit or method, which is lacripey having SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof. 42. The composition, kit or method of any one of claims 1 to 41 wherein the composition does not contain tiloxapol. 43. The composition, kit or method of any one of claims 1 to 42 wherein the composition does not contain EDTA. The composition of claim 1, wherein the composition is in undigested form in the composition after storage of the composition for 1 week at 5 ± 3 ° C. or 25 ± 2 ° C. and at 25 ± 5% relative humidity. Composition, kit or method of maintaining at least about 99.0% polypeptide. The composition of claim 1, wherein the composition is at least about 99.0% in undissolved form in the composition after storage of the composition for two weeks at 25 ± 2 ° C. and 25 ± 5% relative humidity. A composition, kit, or method for maintaining a polypeptide. 46. The composition according to any one of claims 1 to 45, wherein the composition is in undecomposed form in the composition after storage of the composition for one month at 5 ± 3 ° C or 25 ± 2 ° C and 25 ± 5% relative humidity. A composition, kit, or method that maintains at least about 99.0% polypeptide. The composition of claim 1, wherein the composition maintains at least about 99.0% polypeptide in undissolved form in the composition after storage of the composition for 2 months at 5 ± 3 ° C. 49. Kit or method. The composition of claim 1, wherein the composition is at least about 99.0% poly in undissolved form in the composition after storage of the composition for 3 months at 5 ± 3 ° C. or −20 ± 5 ° C. 49. Compositions, kits or methods for holding a peptide. 49. The composition of any one of the preceding claims, wherein the composition maintains at least about 99.0% polypeptide in undissolved form in the composition after storage of the composition for 4 months at 5 ± 3 ° C. Kit or method. The composition of any one of claims 1-49, wherein the composition maintains at least about 99.0% polypeptide in undissolved form in the composition after storage of the composition for 5 months at 5 ± 3 ° C. Kit or method. 51. The composition, kit or method of any one of claims 44-50, wherein the composition maintains at least about 99.5% polypeptide in undissolved form in the composition. 51. The composition, kit or method of any one of claims 44-50, wherein the composition maintains at least about 99.9% polypeptide in undigested form in the composition. 51. The composition, kit or method of any one of claims 44-50, wherein the composition maintains at least about 99.95% polypeptide in undigested form in the composition. The composition of any one of claims 1-53, wherein the composition maintains at least about 80% of the polypeptide in undigested form in the composition after storage of the composition at 5 ± 3 ° C. for 12 months, Kit or method. 55. The composition, kit or method of claim 54, wherein the composition maintains at least about 90% polypeptide in undissolved form in the composition.

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